Professor Darryl Knight
Honorary Professor
School of Biomedical Sciences and Pharmacy
The Science of Breathing
A renowned researcher, Professor Darryl Knight is spearheading medical breakthroughs to make life a little easier for people suffering from a range of respiratory diseases.
Most of us don’t think about breathing until we’re short of breath. We are the lucky ones. For those suffering from a handful of serious medical conditions, however, breathing – and more specifically, an impaired ability to do so – is a concern that frequently prays on the mind. Dedicated to helping this group is Professor Darryl Knight, whose evolving understanding of abnormal repair responses within the lung is contributing to a growing and extensive research knowledge base.
“My aim is to figure out the pathological mechanisms that underpin insidious and sometimes chronic changes to the architecture of the respiratory system,” he elaborates.
“In asthma, this is called airway remodelling.”
“Current therapies target inflammation and symptoms but have no effect on this.”
“The situation is worse with pulmonary fibrosis because the only two drugs that are approved in the world (and not in Australia) for its treatment are unable to halt disease progression.”
Taking a “very circuitous and non-conventional” path, Darryl admits he wanted to be a naturalist before developing an interest in human biology.
“I was first exposed to the lungs when I undertook my Honours project, which looked at the receptors that Ventolin acts on to relax the airways in an asthma attack,” he recalls.
“This curiosity about the respiratory system was piqued during my stint at Sir Charles Gairdner Hospital, where I worked as a research assistant with a chest physician collecting pig lungs from the local abattoir and eventually, human lung tissue from patients undergoing surgery for the removal of cancers.”
“Around this time, the role of the epithelium, which is the thin tissue that forms the outer layer of the body’s surface and lines its hollow internal structures, possibly being more than a physical barrier was being postulated and the first studies showing epithelial damage in asthmatic airways in vivo were published.”
Smooth sailing
Seeking to keep this momentum going, Darryl commenced a PhD at the University of Western Australia in 1989. Building on the findings of his predecessors, the ‘Respirology’ Editor’s groundbreaking in vitro study is widely acknowledged as one of the first to provide a “functional correlate” by showing that the epithelium inhibits airway smooth muscle contraction.
“Originally, my candidature was pharmacology-based,” he shares.
“Segments of human airways were suspended in organ baths and assessed for contraction/relaxation.”
“At the latter stages, however, I crafted molecular and cell biology-based techniques, such as polymerase chain reaction (PCR) to measure gene expression and immunohistochemistry to analyse protein expression.”
Wanting to make his mark professionally both here and abroad, Darryl stayed at the University of Western Australia until 1995 before relocating to the University of British Columbia as a Thoracic Society of Australia and New Zealand (TSANZ)-funded Postdoctoral Fellow. Based at its prestigious Pulmonary Research Laboratory, he spent the next two years investigating the role of the Interleukin-6 family of cytokines in regulating airway function.
“Cytokines are substances that are secreted by cells of the immune system and have an effect on other cells,” he explains.
“Two in particular took my interest during this time – Leukaemia Inhibitory Factor (LIF) and Oncostatin M (OSM).”
“We were able to show for the first time that the former is widely present in many cell types in human lungs, including sensory nerves and eosinophils, and can regulate their function.”
“We also showed that OSM is present in the lung’s structural cells and involved in wound healing and fibrosis.”
Looking to share his expertise, Darryl returned to the University of Western Australia in 1997 and remained there until 2004 before being recruited back to the University of British Columbia as a Canada Research Chair in Airway Disease. He joined the University of Newcastle in January 2013 as the Head of the School of Biomedical Sciences and Pharmacy.
A breath of fresh air
Currently, Darryl is consumed by two main research questions. He’s working to discover how differentiation of the epithelium and fibroblasts contribute to asthma and pulmonary fibrosis, as well as how the lung’s connective tissue regulates the behaviour of epithelial cells and fibroblasts. Both studies are funded by the National Health and Medical Research Council and involve collaboration with several universities around the country.
“In our Asthma program, we’ve teamed up with investigators from the University of Western Australia and are obtaining epithelial cells from children and adults who suffer from the disease,” he reveals.
“We’re examining differentiation in these cells when they are grown in specialised culture conditions, which allow them to form a multi-layered barrier similar to the one occurring in the airways.”
“In our fibrosis research program, we’ve enlisted the help of scholars from the Universities of Sydney, Melbourne and Western Australia as well as the University of Victoria in British Columbia.”
“We are using state-of-the-art technology, called Maldi-imaging, to visualise the relative proportion and spatial distribution of hundreds of proteins in human lung tissue on a microscopic slide.”
“This will enable us to better understand the pathogenesis of pulmonary fibrosis.”
With an equally strong focus on industry partnerships, Darryl is also in the process of conducting a large study with a multinational pharmaceutical company to determine new targets related to the barrier function of the epithelium in asthma and chronic obstructive pulmonary disease (COPD). He is planning to extend his field of study to examine common mechanisms of fibrosis in multiple organs too.
“It’s a really exciting time in respiratory research,” he asserts.
“There’s a lot of work to do.”
The Science of Breathing
Prof Knight’s research program is focused on two independent but interrelated themes designed to increase our understanding of how the abnormal repair responses
Career Summary
Biography
Professor Darryl Knight joins the University of Newcastle as the Head of the School of Biomedical Sciences and Pharmacy. Having received his BSc Honours degree in Pharmacology and his PhD from the University of Western Australia, Prof Knight undertook post-doctoral training at the University of British Columbia from 1995-1997. From 1997 to 2001 he was a Senior Research Officer in the Asthma & Allergy Research Institute (now the Lung Institute of Western Australia) at the University of Western Australia and was Head of the Experimental Biology division of the Institute from 2002-2004. In 2004, Prof Knight was recruited back to the University of British Columbia as the Canada Research Chair in Airway Disease and Associate Professor of Pharmacology. In 2007, Prof Knight was awarded a Michael Smith Foundation for Health Research Senior Scholar Career Investigator award and was named the William Thurlbeck Distinguished Lecturer by the Churg Foundation. He was also chosen as the recipient of funds from an endowment fund made to the University from a prominent local businessman, Peter Dhillon, in memory of his father who died of pulmonary fibrosis. In 2008, and assumed the role of Associate Director of the UBC James Hogg Research Centre and in 2009 was promoted to Full Professor. Prof Knight has had an outstanding research career with over 145 published papers and 3500+ citations (H-index = 40), and is focused on his research interests of pulmonary pharmacology and pathology and how they impact on airway and lung function.
Research Expertise
Prof Knight’s primary fields of teaching and research interest are centered on pulmonary pharmacology and pathology and how they impact on airway and lung function. Asthma and Interstitial lung diseases are his primary research interests. Prof Knight’s research program is focused on two independent but interrelated themes designed to increase our understanding of how the abnormal repair responses within the lung i) develop ii) contribute to the severity and chronicity of disease and iii) impact on treatment. These themes are focused the respiratory epithelium and adjacent fibroblasts. This microenvironment is the critical site for the initiation and perpetuation of the pathologic processes which contribute to fibrotic pulmonary diseases. His research program involves the investigation of two diseases, Asthma and idiopathic pulmonary fibrosis, both of which are intimately associated with remodelling and fibrosis. The research is performed at molecular, cellular levels as well as intact animal models in the belief that no single disease perspective or methodology will yield complete insights into the nature of the interaction between these two cell types. He also links to clinical investigators who bring his work directly into the context of patients suffering from these diseases.
Teaching Expertise
Prof Knight’s teaching experience spans Honours, Masters, and PhD and Post Doctorial students. He supervised students across all of these levels, with many receiving awards and over 90% were self-funded while under his tutelage. He also examined theses and lectured in Pharmacology and Therapeutics at the University of British Columbia from 2004-2012. While at the University of British Columbia, Prof Knight also served on many Graduate Student Advisory Committees and Graduate Student Comprehensive Exam Committees.
Administrative Expertise
Prof Knight has extensive administrative experience, most recently as Associate Director of the James Hogg Research Centre (JHRC) at the University of British Columbia. This role required him to work closely with the Centre Director and executive research leaders team to enhance the quality, quantity and recognition of research at Providence Health Care and the University. Prof Knight was also responsible for human, capital, financial and information resources to ensure that research objectives are achieved, while seeking partnership opportunities and developing strong relationships within the health community. From September-December 2012, Prof Knight filled the role of Interim Director of the JHRC. From 2008-2011, Prof Knight held the position of Chair of the Graduate Program Committee (Department of Anaesthesiology, Pharmacology and Therapeutics). As chair, he was the Graduate Advisor for the department and designed a modular course for graduate students in the department that was implemented in September 2010.
Collaborations
Prof Knight has several ongoing collaborations with investigators locally as well as both nationally and internationally, including laboratories in the United Kingdom, Australia, USA and Mexico. These collaborations are all productive, yielding several manuscripts in high impact factor journals and competitively funded grant applications.
Qualifications
- PhD, University of Western Australia
- Bachelor of Science (Honours), University of Western Australia
Keywords
- Asthma and Interstitial lung diseases
- pulmonary pathology
- pulmonary pharmacology
Professional Experience
Academic appointment
Dates | Title | Organisation / Department |
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1/1/2012 - | Editorial Board - Faculty of 1000 | Faculty of 1000 Australia |
1/1/2011 - | Editor - Experimental Lung Research | Experimental Lung Research Australia |
1/1/2011 - 1/12/2012 | Chair (Basic Science Grant Review Committee) | Canadian Lung Association Canada |
1/1/2010 - | Editor - International Journal Biochemistry and Cell Biology | International Journal Biochemistry and Cell Biology Australia |
1/12/2009 - 1/12/2012 | Research Steering Committee | Canadian Lung Association Canada |
1/1/2009 - | Editor - American Journal of Respiratory Cell and Molecular Biology | American Journal of Respiratory Cell and Molecular Biology United States |
1/1/2009 - | Editor - Respirology | Respirology Australia |
1/1/2008 - 1/12/2011 | Chair (Department of Anesthesiology, Pharmacology and Therapeutics) Graduate Program Committee | University of British Columbia Canada |
1/1/2008 - | Membership - Canadian Thoracic Society | Canadian Thoracic Society Canada |
1/1/2007 - | Editor - Journal of Epithelial Biology and Pharmacology | Journal of Epithelial Biology and Pharmacology Australia |
1/1/2007 - 31/12/2012 | Membership - Institute for Heart and Lung Health Executive Committee | Institute for Heart and Lung Health Australia |
1/1/2006 - 31/12/2011 | Editor - Pulmonary Pharmacology and Therapeutics | Pulmonary Pharmacology and Therapeutics Australia |
1/1/2006 - 31/12/2012 | Membership - Canadian Institutes of Health Research Respiratory System (RS) Grants Committee | Canadian Institutes of Health Research Respiratory System (RS) Grants Committee Canada |
1/1/2004 - 1/1/2013 |
Canada Research Chair in Airway Disease The Canada Research Chairs program |
Government of Canada Canada |
1/1/2004 - 31/12/2007 | Membership - American Society for Biochemistry and Molecular Biology | American Society for Biochemistry and Molecular Biology United States |
1/1/2003 - 31/12/2004 | Membership - National Advisory Committee, Australian Lung Foundation | Lung Foundation Australia |
1/1/2003 - 31/12/2010 | Membership - American Society for Cell Biology | American Society for Cell Biology United States |
1/1/1995 - | Membership - American Thoracic Society | American Thoracic Society United States |
1/1/1991 - 31/12/2005 | Membership - Australian Lung Foundation | Lung Foundation Australia |
1/1/1991 - 31/12/2005 | Membership - Thoracic Society of Australia and New Zealand | Thoracic Society of Australia and New Zealand |
Membership
Dates | Title | Organisation / Department |
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Program Advisory Committee Member and Chair of the HQP Committe - Allergen NCE 6th Annual Research Conference | Program Advisory and Scientific committee Australia |
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Member - Program Advisory and Scientific Committee 16th International Colloquium on Lung and Airway Fibrosis | Program Advisory and Scientific committee Australia |
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Member - Program Advisory and Local Organizing Committee – CIHR/ICRH Young Investigators Forum | Program Advisory and Scientific committee Australia |
Awards
Research Award
Year | Award |
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2010 |
Career Investigator Award (Senior Scholar) Michael Smith Foundation for Health Research |
2007 |
Rashpal Dhillon Fund for Idiopathic Pulmonary Fibrosis (IPF) Research Rashpal Dhillon Fund for Idiopathic Pulmonary Fibrosis (IPR) Research |
2007 |
The William Thurlbeck Distinguished Researcher Award Wolfe and Gita Churg Foundation |
2001 |
New Investigator Infrastructure support award Medical and Health Research Infrastructure Council (MHRIC) |
1998 |
Career Development Award The Australian Lung foundation |
1994 |
Encouragement award for Clinical Research Sandoz Australia |
1994 |
Young Investigator of the Year The Thoracic Society of Australia and New Zealand |
Invitations
Participant
Year | Title / Rationale |
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2013 |
Severe Asthma – Is it also an epithelial disease? Organisation: Thoracic Society of Australia and New Zealand Annual Scientific Conference |
2012 |
Breakout session on future of IPF research Organisation: 17th International Colloquium on Lung and airway fibrosis. |
2012 |
Thematic Poster Session on pathways regulating airway cell differentiation Organisation: American Thoracic Society Annual Scientific Conference Description: |
2012 |
Symposium session on the Regulation of the ECM in lung disease. Organisation: American Thoracic Society Annual Scientific Conference Description: |
2011 |
Insights into the pathogenesis of lung fibrosis and granulomas Organisation: American Thoracic Society Annual Scientific Conference Description: |
2011 |
Thematic Poster Session on pathways Regulating fibroblast gene expression Organisation: American Thoracic Society Annual Scientific Conference Description: |
2011 |
The role of the Epithelium in Chronic Inflammatory Lung Disease Organisation: Spring 2011 Pulmonary Research Group Symposium Description: |
Speaker
Year | Title / Rationale |
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2013 |
The epithelial innate and adaptive immune profile Organisation: AbCam Symposium on Allergy and Asthma |
2013 |
Stem Cells for repair of the human airway epithelium. Organisation: Keystone Symposium on Pathogenic processes in asthma and COPD Description: |
2012 |
The epithelium in asthma – how did it get to be so bad? Organisation: Simon Fraser University Invited Lecture Series Description: |
2012 |
Disturbing Double Entendres: Disrupting the fine control of epithelial differentiation in Asthma Organisation: Meakins-Christie Laboratory 15th Annual International workshop on recent advances in Asthma and COPD Description: |
2012 |
Regenerative Medicine for the treatment of Asthma Organisation: UBC Celebrate Research Week Description: |
2012 |
Fibroblast heterogeneity in lung fibrosis Organisation: Canadian Respiratory Conference Description: |
2012 |
The epithelium in asthma: How not to be an effective barrier. Organisation: Federation of Clinical Immunology Societies (FOCIS) Annual Scientific Conference Description: |
2012 |
Role of gp130/STAT3 in extracellular matrix Organisation: Transatlantic Airway Conference, Lung Injury and Repair |
2012 |
Whats in a STAT? Organisation: Northwestern University Invited Lecture Series Description: |
2012 |
Exogenous control of the ECM, is this an unrealistic goal? Organisation: American Thoracic Society Annual Scientific Conference Description: |
2011 |
The epithelium in asthma – should it just grow up or is it OK as it is? Organisation: University of Calgary, Asthma and Allergy Research Group Description: |
2011 |
Journey to the Centre of the lung in search of a myofibroblasts. Organisation: Meakins-Christie Laboratory 14th Annual International workshop on recent advances in Asthma and COPD Description: |
2011 |
New strategies applied to old cells in IPF. Organisation: Medimmune, Cambridge Description: |
2011 |
When is a myofibroblast not a myofibroblast? Organisation: University of Nottingham Description: |
2011 |
Epithelial differentiation as a novel target for asthma therapy. Organisation: National Heart and Lung Institute Description: |
2011 |
The role of the epithelium in airway remodeling. Organisation: Injury and Repair Mechanisms in Chronic Airway Disease Description: |
2011 |
Epithelial repair and Airway remodeling. Organisation: Pulmonary Research Group Symposium on the Role of the Epithelium in Chronic Inflammatory Lung Disease Description: |
2010 |
Journey to the Centre of the lung in search of a cause for IPF Organisation: Woolcock Institute for Respiratory Medicine |
2010 |
When is a myofibroblast not a myofibroblast? Organisation: 16th International Colloquium on Lung and airway fibrosis Description: |
2010 |
Epigenetic influences on epithelial function in asthma. Organisation: Meakins-Christie Laboratory 13th Annual International workshop on recent advances in Asthma and COPD |
2010 |
Molecular Aspects of the origins of IPF Organisation: BC Lung Health Forum Description: |
Publications
For publications that are currently unpublished or in-press, details are shown in italics.
Book (1 outputs)
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2019 |
Rhinovirus infections: Rethinking the impact on human health and disease, Academic Press, London (2019)
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Chapter (12 outputs)
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2021 |
Knight D, 'Oncostatin M', Encyclopedia of Respiratory Medicine, Second Edition 723-727 (2021) Oncostatin M (OSM) is a multifunctional cytokine secreted as a 28kDa glycoprotein primarily from activated T lymphocytes and macrophages. OSM belongs to the interleukin-6 family t... [more] Oncostatin M (OSM) is a multifunctional cytokine secreted as a 28kDa glycoprotein primarily from activated T lymphocytes and macrophages. OSM belongs to the interleukin-6 family that also includes interleukin-11, leukemia inhibitory factor, ciliary neurotrophic factor, cardiotrophin-1, ¿novel neurotrophin-1/B cell-stimulating factor-3'/cardiotrophin-like cytokine,¿ IL-27, and IL-31. These cytokines are grouped together on the basis of weak sequence homology and shared use of the signal transducing subunit gp130 as part of their receptor complexes. Accordingly, oncostatin M shares properties with all members of this cytokine family, but is most closely related in structure and function to leukemia inhibitory factor. Oncostatin M acts on a variety of cells and displays functions involved in regulating gene activation, cell growth, and inflammatory processes. Despite these functions, investigations into its role in respiratory disease have been limited. Those studies that have been performed suggest that oncostatin M is a potent inducer of anti-proteases, is anti-inflammatory, an immune modifier and promotes the deposition of extracellular matrix proteins. Thus, it is likely that in the lung, oncostatin M may play a prominent role in normal wound healing as well as remodeling and pathological fibrosis.
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2019 |
Reid AT, Sutanto EN, Chander-Veerati P, Looi K, Li NF, Iosifidis T, et al., 'Ground zero-the airway epithelium', Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Academic Press, Cambridge, MS 61-98 (2019) [B1]
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2019 |
Bartlett N, Esneau C, Bochkov Y, 'Rhinovirus structure, replication, and classification', Rhinovirus infections: Rethinking the impact on human health and disease, Elsevier, London 1-23 (2019) [B1]
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2019 |
Wark P, Williams T, Pathinayake P, 'The interplay of the host, virus, and the environment', Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Elsevier, London 169-194 (2019) [B1]
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2019 |
McLean G, Girkin J, Solari R, 'Emerging therapeutic approaches', Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Elsevier, London 239-263 (2019) [B1]
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2014 |
Knight D, Hirota J, 'Airway Epithelial Cells', Middleton's Allergy: Principles and Practice: Eighth Edition 302-314 (2014)
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Journal article (201 outputs)
Year | Citation | Altmetrics | Link | ||||||||
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2023 |
Veerati PC, Reid AT, Nichol KS, Wark PAB, Knight DA, Bartlett NW, Grainge CL, 'Mechanical forces suppress antiviral innate immune responses from asthmatic airway epithelial cells following rhinovirus infection.', Am J Physiol Lung Cell Mol Physiol, 325 L206-L214 (2023) [C1]
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2022 |
Williams TC, Loo S-L, Nichol KS, Reid AT, Veerati PC, Esneau C, et al., 'IL-25 blockade augments antiviral immunity during respiratory virus infection', COMMUNICATIONS BIOLOGY, 5 (2022) [C1]
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2022 |
Veerati PC, Nichol KS, Read JM, Bartlett NW, Wark PAB, Knight DA, et al., 'Conditionally reprogrammed asthmatic bronchial epithelial cells express lower
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2022 |
Kan S, Grainge C, Nichol K, Reid A, Knight D, Sun Y, et al., 'TLR7 agonist loaded airway epithelial targeting nanoparticles stimulate innate immunity and suppress viral replication in human bronchial epithelial cells', INTERNATIONAL JOURNAL OF PHARMACEUTICS, 617 (2022) [C1]
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2022 |
Prêle CM, Miles T, Pearce DR, O'Donoghue RJ, Grainge C, Barrett L, et al., 'Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis.', The European respiratory journal, 60 2101469 (2022) [C1]
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2022 |
Blokland KEC, Nizamoglu M, Habibie H, Borghuis T, Schuliga M, Melgert BN, et al., 'Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts', Frontiers in Pharmacology, 13 [C1]
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2022 |
Tu X, Kim RY, Brown AC, de Jong E, Jones-Freeman B, Ali MK, et al., 'Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap', Journal of Allergy and Clinical Immunology, 150 817-829.e6 (2022) [C1] Background: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COP... [more] Background: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied. Objectives: This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure. Methods: Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313. Results: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO. Conclusions: A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.
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2021 |
Kuchibhotla VNS, Starkey MR, Reid AT, Heijink IH, Nawijn MC, Hansbro PM, Knight DA, 'Inhibition of beta-Catenin/CREB Binding Protein Signaling Attenuates House Dust Mite-Induced Goblet Cell Metaplasia in Mice', FRONTIERS IN PHYSIOLOGY, 12 (2021) [C1]
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2021 |
Blokland KEC, Habibie H, Borghuis T, Teitsma GJ, Schuliga M, Melgert BN, et al., 'Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM', CELLS, 10 (2021) [C1]
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2021 |
Looi K, Larcombe AN, Perks KL, Berry LJ, Zosky GR, Rigby P, et al., 'Previous influenza infection exacerbates allergen specific response and impairs airway barrier integrity in pre-sensitized mice', International Journal of Molecular Sciences, 22 (2021) [C1] In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight ... [more] In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction ex-pression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosino-phils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where in-fluenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.
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2021 |
Girkin J, Loo S-L, Esneau C, Maltby S, Mercuri F, Chua B, et al., 'TLR2-mediated innate immune priming boosts lung anti-viral immunity', EUROPEAN RESPIRATORY JOURNAL, 58 (2021) [C1]
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2021 |
Schuliga M, Kanwal A, Read J, Blokland KEC, Burgess JK, Prele CM, et al., 'A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 321 L859-L871 (2021) [C1]
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2021 |
Schuliga M, Read J, Knight DA, 'Ageing mechanisms that contribute to tissue remodeling in lung disease', AGEING RESEARCH REVIEWS, 70 (2021) [C1]
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2021 |
Shahangian K, Ngan DA, Chen HHR, Oh Y, Tam A, Wen J, et al., 'IL-4Ra blockade reduces influenza-associated morbidity in a murine model of allergic asthma', Respiratory Research, 22 (2021) [C1] Background: Asthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic a... [more] Background: Asthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor a (IL-4Ra), a critical mediator of Th2 signalling, improved their outcomes. Methods: Male BALB/c mice were intranasally sensitized with house dust mite antigen (Der p 1) for 2¿weeks; the mice were then inoculated intranasally with a single dose of pandemic H1N1 (pH1N1). The mice were administered intraperitoneally anti-IL-4Ra through either a prophylactic or a therapeutic treatment strategy. Results: Infection with pH1N1 of mice sensitized to house dust mite (HDM) led to a 24% loss in weight by day 7 of infection (versus 14% in non-sensitized mice; p <.05). This was accompanied by increased viral load in the airways and a dampened anti-viral host responses to the infection. Treatment of HDM sensitized mice with a monoclonal antibody against IL-4Ra prior to or following pH1N1 infection prevented the excess weight loss, reduced the viral load in the lungs and ameliorated airway eosinophilia and systemic inflammation related to the pH1N1 infection. Conclusion: Together, these data implicate allergic asthma as a significant risk factor for H1N1-related morbidity and reveal a potential therapeutic role for IL-4Ra signalling blockade in reducing the severity of influenza infection in those with allergic airway disease.
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2021 |
Iosifidis T, Sutanto EN, Montgomery ST, Agudelo-Romero P, Looi K, Ling KM, et al., 'Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze', Journal of Personalized Medicine, 11 (2021) [C1] The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by... [more] The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.
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2021 |
Prêle CM, Iosifidis T, McAnulty RJ, Pearce DR, Badrian B, Miles T, et al., 'Reduced socs1 expression in lung fibroblasts from patients with ipf is not mediated by promoter methylation or mir155', Biomedicines, 9 (2021) [C1] The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) ... [more] The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5'-aza-2'-deoxycytidine¿ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function.
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2021 |
Waters DW, Schuliga M, Pathinayake PS, Wei L, Tan H-Y, Blokland KEC, et al., 'A Senescence Bystander Effect in Human Lung Fibroblasts', BIOMEDICINES, 9 (2021) [C1]
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2021 |
Goggins BJ, Minahan K, Sherwin S, Soh WS, Pryor J, Bruce J, et al., 'Pharmacological HIF-1 stabilization promotes intestinal epithelial healing through regulation of alpha-integrin expression and function', AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 320 G420-G438 (2021) [C1]
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2020 |
Schuliga M, Read J, Blokland KEC, Waters DW, Burgess J, Prele C, et al., 'Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner', CLINICAL SCIENCE, 134 889-905 (2020) [C1]
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2020 |
Veerati PC, Mitchel JA, Reid AT, Knight DA, Bartlett NW, Park JA, Grainge CL, 'Airway mechanical compression: Its role in asthma pathogenesis and progression', European Respiratory Review, 29 1-13 (2020) [C1]
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2020 |
Kuchibhotla VNS, Jonker MR, de Bruin HG, Noordhoek JA, Knight DA, Nawijn MC, Heijink IH, 'Inhibition of ß-catenin/CBP signalling improves airway epithelial barrier function and suppresses CCL20 release', Allergy: European Journal of Allergy and Clinical Immunology, 75 1786-1789 (2020) [C1]
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2020 |
Kicic A, de Jong E, Ling K-M, Nichol K, Anderson D, Wark PAB, et al., 'Assessing the unified airway hypothesis in children via transcriptional profiling of the airway epithelium', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 145 1562-1573 (2020) [C1]
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2020 |
Reid AT, Nichol KS, Veerati PC, Moheimani F, Kicic A, Stick SM, et al., 'Blocking notch3 signaling abolishes MUC5AC production in airway epithelial cells from individuals with asthma', American Journal of Respiratory Cell and Molecular Biology, 62 513-523 (2020) [C1] In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more difficult to clear and results in airway mucus pluggin... [more] In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more difficult to clear and results in airway mucus plugging. Notch1, Notch2, or Notch3, or a combination of these has been shown to influence the differentiation of airway epithelial cells. How the expression of specific Notch isoforms differs in fully differentiated adult asthmatic epithelium and whether Notch influences mucin production after differentiation is currently unknown. We aimed to quantify different Notch isoforms in the airway epithelium of individuals with severe asthma and to examine the impact of Notch signaling on mucin MUC5AC. Human lung sections and primary bronchial epithelial cells from individuals with and without asthma were used in this study. Primary bronchial epithelial cells were differentiated at the air-liquid interface for 28 days. Notch isoform expression was analyzed by Taqman quantitative PCR. Immunohistochemistry was used to localize and quantify Notch isoforms in human airway sections. Notch signaling was inhibited in vitro using dibenzazepine or Notch3-specific siRNA, followed by analysis of MUC5AC. NOTCH3 was highly expressed in asthmatic airway epithelium compared with nonasthmatic epithelium. Dibenzazepine significantly reduced MUC5AC production in air-liquid interface cultures of primary bronchial epithelial cells concomitantly with suppression of NOTCH3 intracellular domain protein. Specific knockdown using NOTCH3 siRNA recapitulated the dibenzazepine-induced reduction in MUC5AC. We demonstrate that NOTCH3 is a regulator of MUC5AC production. Increased NOTCH3 signaling in the asthmatic airway epithelium may therefore be an underlying driver of excess MUC5AC production.
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2020 |
Blokland KEC, Waters DW, Schuliga M, Read J, Pouwels SD, Grainge CL, et al., 'Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing', PHARMACEUTICS, 12 (2020) [C1]
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2020 |
Heijink IH, Kuchibhotla VNS, Roffel MP, Maes T, Knight DA, Sayers I, Nawijn MC, 'Epithelial cell dysfunction, a major driver of asthma development', Allergy: European Journal of Allergy and Clinical Immunology, 75 1898-1913 (2020) [C1] Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly inter... [more] Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.
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2020 |
Knight DA, Grainge CL, Stick SM, Kicic A, Schuliga M, 'Epithelial Mesenchymal Transition in Respiratory Disease: Fact or Fiction', Chest, 157 1591-1596 (2020) [C1]
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2020 |
Iosifidis T, Sutanto EN, Buckley AG, Coleman L, Gill EE, Lee AH, et al., 'Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze', JCI Insight, 5 (2020) [C1]
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2020 |
Veerati PC, Troy NM, Reid AT, Li NF, Nichol KS, Kaur P, et al., 'Airway Epithelial Cell Immunity Is Delayed During Rhinovirus Infection in Asthma and COPD', FRONTIERS IN IMMUNOLOGY, 11 (2020) [C1]
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2020 |
Blokland KEC, Pouwels SD, Schuliga M, Knight DA, Burgess JK, 'Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases', Clinical Science, 134 2681-2706 (2020) [C1]
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2020 |
Kan S, Hariyadi DM, Grainge C, Knight DA, Bartlett NW, Liang M, 'Airway epithelial-targeted nanoparticles for asthma therapy', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 318 L500-L509 (2020) [C1]
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2019 |
Murtha L, Morten M, Schuliga M, Mabotuwana N, Hardy S, Waters D, et al., 'The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis', Aging and Disease, 10 419-428 (2019) [C1]
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2019 |
Liu G, Cooley MA, Jarnicki AG, Borghuis T, Nair PM, Tjin G, et al., 'Fibulin-1c regulates transforming growth factor-beta activation in pulmonary tissue fibrosis', JCI INSIGHT, 4 (2019) [C1]
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2019 |
Waters DW, Blokland KEC, Pathinayake PS, Wei L, Schuliga M, Jaffar J, et al., 'STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts.', Am J Respir Cell Mol Biol, 61 61-73 (2019) [C1]
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2018 |
Fonceca AM, Zosky GR, Bozanich EM, Sutanto EN, Kicic A, McNamara PS, et al., 'Accumulation mode particles and LPS exposure induce TLR-4 dependent and independent inflammatory responses in the lung', Respiratory Research, 19 (2018) [C1]
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2018 |
Reid AT, Veerati PC, Gosens R, Bartlett NW, Wark PA, Grainge CL, et al., 'Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches', Pharmacology and Therapeutics, 185 155-169 (2018) [C1] Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, ... [more] Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
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2018 |
Waters DW, Blokland KEC, Pathinayake PS, Burgess JK, Mutsaers SE, Prele CM, et al., 'Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis', American Journal of Physiology - Lung Cellular and Molecular Physiology, 315 L162-L172 (2018) [C1] Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneu monia of unknown cause with a median survival of only three years. Little is known about the mechanism... [more] Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneu monia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype.
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2018 |
Schuliga M, Pechkovsky DV, Read J, Waters DW, Blokland KEC, Reid AT, et al., 'Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 22 5847-5861 (2018) [C1]
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2018 |
Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, et al., 'Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations', NATURE COMMUNICATIONS, 9 (2018) [C1]
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2018 |
Looi K, Buckley AG, Rigby PJ, Garratt LW, Iosifidis T, Zosky GR, et al., 'Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma', Clinical and Experimental Allergy, 48 513-524 (2018) [C1]
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2018 |
Ghavami S, Yeganeh B, Zeki AA, Shojaei S, Kenyon NJ, Ott S, et al., 'Autophagy and the unfolded protein response promote profibrotic effects of TGF-ß
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2018 |
Schuliga M, Grainge C, Westall G, Knight D, 'The fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis', International Journal of Biochemistry and Cell Biology, 97 108-117 (2018) [C1] Fibrosis causes irreversible damage to lung structure and function in restrictive lung diseases such as idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving fi... [more] Fibrosis causes irreversible damage to lung structure and function in restrictive lung diseases such as idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving fibrin formation in the intra-alveolar compartment is postulated to have a pivotal role in the development of pulmonary fibrosis, serving as a provisional matrix for migrating fibroblasts. Furthermore, proteases of the coagulation and plasminogen activation (plasminergic) systems that form and breakdown fibrin respectively directly contribute to pulmonary fibrosis. The coagulants, thrombin and factor Xa (FXa) evoke fibrogenic effects via cleavage of the N-terminus of protease-activated receptors (PARs). Whilst the formation and activity of plasmin, the principle plasminergic mediator is suppressed in the airspaces of patients with IPF, localized increases are likely to occur in the lung interstitium. Plasmin-evoked proteolytic activation of factor XII (FXII), matrix metalloproteases (MMPs) and latent, matrix-bound growth factors such as epidermal growth factor (EGF) indirectly implicate plasmin in pulmonary fibrosis. Another plasminergic protease, urokinase plasminogen activator (uPA) is associated with regions of fibrosis in the remodelled lung of IPF patients and elicits fibrogenic activity via binding its receptor (uPAR). Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. This review describes the mechanisms by which components of the two systems primarily involved in fibrin homeostasis contribute to interstitial fibrosis, with a particular focus on IPF. Selectively targeting the receptor-mediated mechanisms of coagulant and plasminergic proteases may limit pulmonary fibrosis, without the bleeding complications associated with conventional anti-coagulant and thrombolytic therapies.
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2018 |
Moheimani F, Koops J, Williams T, Reid AT, Hansbro PM, Wark PA, Knight DA, 'Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics', Respiratory Research, 19 (2018) [C1]
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2018 |
Buckley AG, Looi K, Iosifidis T, Ling KM, Sutanto EN, Martinovich KM, et al., 'Visualisation of Multiple Tight Junctional Complexes in Human Airway Epithelial Cells', Biological Procedures Online, 20 1-9 (2018) [C1]
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2017 |
Hansbro PM, Kim RY, Starkey MR, Donovan C, Dua K, Mayall JR, et al., 'Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma', Immunological Reviews, 278 41-62 (2017) [C1] Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with... [more] Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
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2017 |
Mahmood MQ, Reid D, Ward C, Muller HK, Knight DA, Sohal SS, Walters EH, 'Transforming growth factor (TGF) ß
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2017 |
Murray LA, Grainge C, Wark PA, Knight DA, 'Use of biologics to treat acute exacerbations and manage disease in asthma, COPD and IPF', Pharmacology and Therapeutics, 169 1-12 (2017) [C1] A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby ... [more] A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disease management. The underlying cause of an acute exacerbation can be due to insults such as pathogens or environmental pollutants, or the cause can be unknown. For each acute exacerbation, the patient may require medical intervention such as rescue medication, or in more severe cases, hospitalization and ventilation and have an increased risk of death. Biologics, such as monoclonal antibodies, are being developed for chronic respiratory diseases including asthma, COPD and IPF. This therapeutic approach is particularly well suited for chronic use based on the route and frequency of delivery and importantly, the potential for disease modification. In recent clinical trials, the frequency of acute exacerbation has often been included as an endpoint, to help determine whether the investigational agent is impacting disease. Therefore the significance of acute exacerbations in driving disease, and their potential as a marker of disease activity and progression, has recently received much attention. There is also now a need to standardize the definition of an acute exacerbation in specific disease settings, particularly as this endpoint is increasingly used in clinical trials to also assess therapeutic efficacy. Moreover, specifically targeting exacerbations may offer a new therapeutic approach for several chronic respiratory diseases.
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2017 |
Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, et al., 'The processes and mechanisms of cardiac and pulmonary fibrosis', Frontiers in Physiology, 8 1-15 (2017) [C1]
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2017 |
Stefanowicz D, Ullah J, Lee K, Shaheen F, Olumese E, Fishbane N, et al., 'Epigenetic modifying enzyme expression in asthmatic airway epithelial cells and fibroblasts', BMC Pulmonary Medicine, 17 (2017) [C1]
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2017 |
Schuliga M, Jaffar J, Harris T, Knight DA, Westall G, Stewart AG, 'The fibrogenic actions of lung fibroblast-derived urokinase: A potential drug target in IPF', Scientific Reports, 7 1-11 (2017) [C1]
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2017 |
Martinovich KM, Iosifidis T, Buckley AG, Looi K, Ling KM, Sutanto EN, et al., 'Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics', Scientific Reports, 7 (2017) [C1]
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2017 |
Habiel DM, Camelo A, Espindola M, Burwell T, Hanna R, Miranda E, et al., 'Divergent roles for Clusterin in Lung Injury and Repair', SCIENTIFIC REPORTS, 7 (2017) [C1]
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2017 |
Pinkerton JW, Kim RY, Robertson AAB, Hirota JA, Wood LG, Knight DA, et al., 'Inflammasomes in the lung', Molecular Immunology, 86 44-55 (2017) [C1] Innate immune responses act as first line defences upon exposure to potentially noxious stimuli. The innate immune system has evolved numerous intracellular and extracellular rece... [more] Innate immune responses act as first line defences upon exposure to potentially noxious stimuli. The innate immune system has evolved numerous intracellular and extracellular receptors that undertake surveillance for potentially damaging particulates. Inflammasomes are intracellular innate immune multiprotein complexes that form and are activated following interaction with these stimuli. Inflammasome activation leads to the cleavage of pro-IL-1ß and release of the pro-inflammatory cytokine, IL-1ß, which initiates acute phase pro-inflammatory responses, and other responses are also involved (IL-18, pyroptosis). However, excessive activation of inflammasomes can result in chronic inflammation, which has been implicated in a range of chronic inflammatory diseases. The airways are constantly exposed to a wide variety of stimuli. Inflammasome activation and downstream responses clears these stimuli. However, excessive activation may drive the pathogenesis of chronic respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. Thus, there is currently intense interest in the role of inflammasomes in chronic inflammatory lung diseases and in their potential for therapeutic targeting. Here we review the known associations between inflammasome-mediated responses and the development and exacerbation of chronic lung diseases.
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2017 |
Murray LA, Habiel DM, Hohmann M, Camelo A, Shang H, Zhou Y, et al., 'Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis', JCI Insight, 2 (2017) The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired ... [more] The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell¿derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium.
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2017 |
Schuliga M, Jaffar J, Berhan A, Langenbach S, Harris T, Waters D, et al., 'Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity', American Journal of Physiology - Lung Cellular and Molecular Physiology, 312 L772-L782 (2017) [C1] In lung injury and disease, including idiopathic pulmonary fibrosis (IPF), extravascular factor X is converted into factor Xa (FXa), a coagulant protease with fibrogenic actions. ... [more] In lung injury and disease, including idiopathic pulmonary fibrosis (IPF), extravascular factor X is converted into factor Xa (FXa), a coagulant protease with fibrogenic actions. Extracellular annexin A2 binds to FXa, augmenting activation of the protease-activated receptor-1 (PAR-1). In this study, the contribution of annexin A2 in lung injury and fibrosis was investigated. Annexin A2 immunoreactivity was observed in regions of fibrosis, including those associated with fibroblasts in lung tissue of IPF patients. Furthermore, annexin A2 was detected in the conditioned media and an EGTA membrane wash of human lung fibroblast (LF) cultures. Incubation with human plasma (5% vol/vol) or purified FXa (15¿50 nM) evoked fibrogenic responses in LF cultures, with FXa increasing interleukin-6 (IL-6) production and cell number by 270 and 46%, respectively (P < 0.05, n = 5¿8). The fibrogenic actions of plasma or FXa were attenuated by the selective FXa inhibitor apixaban (10 µM, or antibodies raised against annexin A2 or PAR-1 (2 µg/ml). FXastimulated LFs from IPF patients (n = 6) produced twice as much IL-6 as controls (n = 10) (P < 0.05), corresponding with increased levels of extracellular annexin A2. Annexin A2 gene deletion in mice reduced bleomycin-induced increases in bronchoalveolar lavage fluid (BALF) IL-6 levels and cell number (*P < 0.05; n = 4¿12). Lung fibrogenic gene expression and dry weight were reduced by annexin A2 gene deletion, but lung levels of collagen were not. Our data suggest that annexin A2 contributes to lung injury and fibrotic disease by mediating the fibrogenic actions of FXa. Extracellular annexin A2 is a potential target for the treatment of IPF.
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2017 |
Huff RD, Hsu ACY, Nichol KS, Jones B, Knight DA, Wark PAB, et al., 'Regulation of xanthine dehydrogensase gene expression and uric acid production in human airway epithelial cells', PLoS ONE, 12 1-17 (2017) [C1]
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2017 |
Jones B, Donovan C, Liu G, Gomez HM, Chimankar V, Harrison CL, et al., 'Animal models of COPD: What do they tell us?', Respirology, 22 21-32 (2017) [C1] COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progr... [more] COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
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2017 |
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
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2017 |
Murray LA, Dunmore R, Camelo A, Da Silva CA, Gustavsson MJ, Habiel DM, et al., 'Acute cigarette smoke exposure activates apoptotic and inflammatory programs but a second stimulus is required to induce epithelial to mesenchymal transition in COPD epithelium', Respiratory Research, 18 (2017) [C1]
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2017 |
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al., 'Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma', American Journal of Respiratory and Critical Care Medicine, 196 283-297 (2017) [C1] Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identifica... [more] Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
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2016 |
Kim RY, Rae B, Neal R, Donovan C, Pinkerton J, Balachandran L, et al., 'Elucidating novel disease mechanisms in severe asthma', CLINICAL & TRANSLATIONAL IMMUNOLOGY, 5 (2016) [C1]
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2016 |
Kicic A, Stevens PT, Sutanto EN, Kicic-Starcevich E, Ling KM, Looi K, et al., 'Impaired airway epithelial cell responses from children with asthma to rhinoviral infection', Clinical and Experimental Allergy, 46 1441-1455 (2016) [C1] Background: The airway epithelium forms an effective immune and physical barrier that is essential for protecting the lung from potentially harmful inhaled stimuli including virus... [more] Background: The airway epithelium forms an effective immune and physical barrier that is essential for protecting the lung from potentially harmful inhaled stimuli including viruses. Human rhinovirus (HRV) infection is a known trigger of asthma exacerbations, although the mechanism by which this occurs is not fully understood. Objective: To explore the relationship between apoptotic, innate immune and inflammatory responses to HRV infection in airway epithelial cells (AECs) obtained from children with asthma and non-asthmatic controls. In addition, to test the hypothesis that aberrant repair of epithelium from asthmatics is further dysregulated by HRV infection. Methods: Airway epithelial brushings were obtained from 39 asthmatic and 36 non-asthmatic children. Primary cultures were established and exposed to HRV1b and HRV14. Virus receptor number, virus replication and progeny release were determined. Epithelial cell apoptosis, IFN-ß production, inflammatory cytokine release and epithelial wound repair and proliferation were also measured. Results: Virus proliferation and release was greater in airway epithelial cells from asthmatics but this was not related to the number of virus receptors. In epithelial cells from asthmatic children, virus infection dampened apoptosis, reduced IFN-ß production and increased inflammatory cytokine production. HRV1b infection also inhibited wound repair capacity of epithelial cells isolated from non-asthmatic children and exaggerated the defective repair response seen in epithelial cells from asthmatics. Addition of IFN-ß restored apoptosis, suppressed virus replication and improved repair of airway epithelial cells from asthmatics but did not reduce inflammatory cytokine production. Conclusions: Collectively, HRV infection delays repair and inhibits apoptotic processes in epithelial cells from non-asthmatic and asthmatic children. The delayed repair is further exaggerated in cells from asthmatic children and is only partially reversed by exogenous IFN-ß.
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2016 |
Haw TJ, Starkey MR, Nair PM, Pavlidis S, Liu G, Nguyen DH, et al., 'A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease', Mucosal Immunology, 9 859-872 (2016) [C1] Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective ... [more] Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-Type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL + CD11b + monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
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2016 |
Koopmans T, Crutzen S, Menzen MH, Halayko AJ, Hackett TL, Knight DA, Gosens R, 'Selective targeting of CREB-binding protein/ß-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle', British Journal of Pharmacology, 173 3327-3341 (2016) [C1] Background and Purpose: Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). ß-catenin, a transcrip... [more] Background and Purpose: Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). ß-catenin, a transcriptional co-activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling. Experimental Approach: We assessed the ability of small-molecule compounds that selectively target ß-catenin breakdown or its interactions with transcriptional co-activators to inhibit airway smooth muscle remodelling in vitro and in vivo. Key Results: ICG-001, a small-molecule compound that inhibits the ß-catenin/CREB-binding protein (CBP) interaction, strongly and dose-dependently inhibited serum-induced smooth muscle growth and TGFß1-induced production of extracellular matrix components in vitro. Inhibition of ß-catenin/p300 interactions using IQ-1 or inhibition of tankyrase 1/2 using XAV-939 had considerably less effect. In a mouse model of allergic asthma, ß-catenin expression in the smooth muscle layer was found to be unaltered in control versus ovalbumin-treated animals, a pattern that was found to be similar in smooth muscle within biopsies taken from asthmatic and non-asthmatic donors. However, ß-catenin target gene expression was highly increased in response to ovalbumin; this effect was prevented by topical treatment with ICG-001. Interestingly, ICG-001 dose-dependently reduced airway smooth thickness after repeated ovalbumin challenge, but had no effect on the deposition of collagen around the airways, mucus secretion or eosinophil infiltration. Conclusions and Implications: Together, our findings highlight the importance of ß-catenin/CBP signalling in the airways and suggest ICG-001 may be a new therapeutic approach to treat airway smooth muscle remodelling in asthma.
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2016 |
Ling KM, Sutanto EN, Iosifidis T, Kicic-Starcevich E, Looi K, Garratt LW, et al., 'Reduced transforming growth factor ß1 (TGF-ß1) in the repair of airway epithelial cells of children with asthma', Respirology, 21 1219-1226 (2016) [C1] Background and objective: Evidence into the role of TGF-ß1 in airway epithelial repair in asthma is still controversial. This study tested the hypothesis that the reduced TGF-ß1 l... [more] Background and objective: Evidence into the role of TGF-ß1 in airway epithelial repair in asthma is still controversial. This study tested the hypothesis that the reduced TGF-ß1 levels previously observed in paediatric asthmatic airway epithelial cells directly contribute to the dysregulated repair seen in these cells. Methods: Primary airway epithelial cells (pAEC) from children with asthma (n = 16) and non-asthmatic subjects (n = 20) were isolated, and subcultured for investigation of TGF-ß1 gene and protein via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Expression of other associated genes such as integrins avß6, avß8 and MT1-MMP were also tested. Small interfering RNA (siRNA) was employed to assess the role of TGF-ß1 during wound repair. Results: TGF-ß1 gene and protein expression were significantly downregulated in asthmatic pAEC over the course of repair, compared with cells from non-asthmatic children. Messenger RNA (mRNA) expression of TGF-ß1 was also directly implicated in non-asthmatic and asthmatic pAEC proliferation over their quiescent counterparts. Small interfering RNA-mediated knockdown of TGF-ß1 compromised repair in non-asthmatic pAEC and exacerbated the dysregulated repair seen in asthmatic pAEC. Expression of major TGF-ß1 activators of epithelial cells, integrin avß6 and avß8 was also measured and there was no difference in avß6 gene expression between the two cohorts. Although integrin avß8 gene expression was significantly higher in asthmatic pAEC, the expression of MT1-MMP (MMP14) which facilitates the avß8 mediated TGF-ß1 activation was significantly downregulated. Conclusion: Our data has highlighted the importance of TGF-ß1 in pAEC wound repair in vitro. The significantly lower levels seen in asthmatic pAEC subsequently contributes to the dysregulated repair observed in these cells.
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2016 |
Garratt LW, Sutanto EN, Ling K-M, Looi K, Iosifidis T, Martinovich KM, et al., 'Alpha-1 Antitrypsin Mitigates the Inhibition of Airway Epithelial Cell Repair by Neutrophil Elastase', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 54 341-349 (2016) [C1]
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2016 |
Iosifidis T, Garratt LW, Coombe DR, Knight DA, Stick SM, Kicic A, 'Airway epithelial repair in health and disease: Orchestrator or simply a player?', Respirology, 21 439-448 (2016) [C1] Epithelial cells represent the most important surface of contact in the body and form the first line of defence of the body to external environment. Consequently, epithelia have n... [more] Epithelial cells represent the most important surface of contact in the body and form the first line of defence of the body to external environment. Consequently, epithelia have numerous roles in order to maintain a homeostatic defence barrier. Although the epithelium has been extensively studied over several decades, it remains the focus of new research, indicating a lack of understanding that continues to exist around these cells in specific disease settings. Importantly, evidence is emerging that airway epithelial cells in particular have varied complex functions rather than simple passive roles. One area of current interest is its role following injury. In particular, the epithelial-specific cellular mechanisms regulating their migration during wound repair remain poorly understood and remain an area that requires much needed investigation. A better understanding of the physiological, cellular and molecular wound repair mechanisms could assist in elucidating pathological processes that contribute to airway epithelial pathology. This review attempts to highlight migration-specific and cell-extracellular matrix (ECM) aspects of repair used by epithelial cells under normal and disease settings, in the context of human airways.
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2016 |
Gold MJ, Hiebert PR, Park HY, Stefanowicz D, Le A, Starkey MR, et al., 'Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization', Mucosal Immunology, 9 809-820 (2016) [C1] Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contrib... [more] Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM 10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM 10 -induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.
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2016 |
Hsu ACY, Parsons K, Moheimani F, Knight DA, Hansbro PM, Fujita T, Wark PA, 'Impaired antiviral stress granule and IFN-ß enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium', American Journal of Respiratory Cell and Molecular Biology, 55 117-127 (2016) [C1] Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infection... [more] Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-ß) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFNinductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-ß enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-ß induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-ß in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-ß in COPD pBECs upon influenza infection.
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2016 |
Searles A, Doran C, Attia J, Knight D, Wiggers J, Deeming S, et al., 'An approach to measuring and encouraging research translation and research impact', HEALTH RESEARCH POLICY AND SYSTEMS, 14 (2016) [C1]
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2016 |
Looi K, Troy NM, Garratt LW, Iosifidis T, Bosco A, Buckley AG, et al., 'Effect of human rhinovirus infection on airway epithelium tight junction protein disassembly and transepithelial permeability', Experimental Lung Research, 42 380-395 (2016) [C1] Rationale: No studies have assessed the effects of human rhinovirus (HRV) infection on epithelial tight junctions (TJs) and resultant barrier function. Aim of the Study: To correl... [more] Rationale: No studies have assessed the effects of human rhinovirus (HRV) infection on epithelial tight junctions (TJs) and resultant barrier function. Aim of the Study: To correlate viral infection with TJ disassembly, epithelial barrier integrity, and function. Materials and Methods: Human airway epithelial cells were infected with HRV minor serotype 1B (HRV-1B) at various 50% tissue culture infectivity doses (TCID50) over 72¿hours. HRV replication was assessed by quantitative-polymerase chain reaction (qPCR) while cell viability and apoptosis were assessed by proliferation and apoptotic assays, respectively. Protein expression of claudin-1, occludin, and zonula occludens protein-1 (ZO-1) was assessed using In-Cell¿ Western assays. Transepithelial permeability assays were performed to assess effects on barrier functionality. RT2 Profiler focused qPCR arrays and pathway analysis evaluating associations between human TJ and antiviral response were performed to identify potential interactions and pathways between genes of interests. Results: HRV-1B infection affected viability that was both time and TCID50 dependent. Significant increases in apoptosis and viral replication post-infection correlated with viral titer. Viral infection significantly decreased claudin-1 protein expression at the lower TCID50, while a significant decrease in all three TJ protein expressions occurred at higher TCID50. Decrease in protein expression was concomitant with significant increases in epithelial permeability of fluorescein isothiocynate labeled-dextran 4 and 20¿kDa. Analysis of focused qPCR arrays demonstrated a significant decrease in ZO-1 gene expression. Furthermore, network analysis between human TJ and antiviral response genes revealed possible interactions and regulation of TJ genes via interleukin (IL)-15 in response to HRV-1B infection. Conclusion: HRV-1B infection directly alters human airway epithelial TJ expression leading to increased epithelial permeability potentially via an antiviral response of IL-15.
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2016 |
Gang L, Hsu A, Cooley MA, Jarnicki AG, Nair PM, Haw TJ, et al., 'Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases', Journal of Clinical Investigation Insight, 1 (2016) [C1]
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2016 |
Moheimani F, Hsu AC-Y, Reid AT, Williams T, Kicic A, Stick SM, et al., 'The genetic and epigenetic landscapes of the epithelium in asthma', RESPIRATORY RESEARCH, 17 (2016) [C1]
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2015 |
Hirota JA, Marchant DJ, Singhera GK, Moheimani F, Dorscheid DR, Carlsten C, et al., 'Urban particulate matter increases human airway epithelial cell IL-1 beta secretion following scratch wounding and H1N1 influenza A exposure in vitro', EXPERIMENTAL LUNG RESEARCH, 41 353-362 (2015) [C1]
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2015 |
Sohal SS, Mahmood MQ, Shukla SD, Hardikar AA, Noor WD, Muller HK, et al., 'Epithelial mesenchymal transition (EMT) in small and large airways of smokers; and relation to airflow obstruction', EUROPEAN RESPIRATORY JOURNAL, 46 (2015)
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2015 |
Carthy JM, Meredith AJ, Boroomand S, Abraham T, Luo Z, Knight D, McManus BM, 'Versican V1 Overexpression Induces a Myofibroblast-Like Phenotype in Cultured Fibroblasts.', PLoS One, 10 e0133056 (2015) [C1]
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2015 |
Moheimani F, Roth HM, Cross J, Reid AT, Shaheen F, Warner SM, et al., 'Disruption of ß-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair', International Journal of Biochemistry and Cell Biology, 68 59-69 (2015) [C1] The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relativel... [more] The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor ß-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the ß-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the ß-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the ß-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFß1 in the presence or absence of the selective small molecule ICG-001 to inhibit ß-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, ß-catenin, fibronectin and ITGß1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFß1 induced EMT, characterized by reduced E-cadherin expression with increased expression of a-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFß1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFß1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGß1 and fibronectin expression. These data support our hypothesis that modulating the ß-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.
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2015 |
Hatchwell L, Collison A, Girkin J, Parsons K, Li J, Zhang J, et al., 'Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia', Thorax, (2015) [C1] © 2015 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), w... [more] © 2015 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood. Objectives To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection. Methods Wild-type and TLR7-deficient (Tlr7<sup>-/-</sup>) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC). Results Allergic Tlr7<sup>-/-</sup> mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFN? release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFN?2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils. Conclusions This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.
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2015 |
Hsu ACY, Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, et al., 'Targeting PI3K-p110a suppresses influenza virus infection in chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 191 1012-1023 (2015) [C1] Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which ... [more] Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting. Methods: We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and Main Results: COPDpBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110a levels and activity inCOPDpBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110a inhibitors, or exogenous IFN-b restored protective antiviral responses, suppressed infection, and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110a activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
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2015 |
Mahmood MQ, Sohal SS, Shukla SD, Ward C, Hardikar A, Noor WD, et al., 'Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction', INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, 10 1515-1524 (2015) [C1]
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2015 |
Stefanowicz D, Lee JY, Lee K, Shaheen F, Koo HK, Booth S, et al., 'Elevated H3K18 acetylation in airway epithelial cells of asthmatic subjects', Respiratory Research, 16 (2015) [C1] Background: Epigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permiss... [more] Background: Epigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permissive or repressive to gene expression. Epigenetic regulation of gene expression is cell specific and therefore, it is important to understand its contribution to individual cellular responses in tissues like the airway epithelium which forms the mucosal barrier to the inhaled environment within the lung. The airway epithelium of asthmatics is abnormal with dysregulation of genes such as epidermal growth factor receptor (EGFR), the dN isoform of the transcription factor p63 (dNp63), and signal transducer and activator of transcription 6 (STAT6), integral to differentiation, proliferation, and inflammation. It is important to establish in diseases like asthma how histone modifications affect tissue responses such as proliferation and differentiation. Objectives: To characterize the global histone acetylation and methylation status in the epithelium of asthmatic compared to healthy subjects and to identify the impact of these variations on genes involved in epithelial functions. Methods: Whole lungs were obtained from healthy and asthmatic subjects (n = 6) from which airway epithelial cells (AECs) were isolated and airway sections were taken for analysis of histone lysine acetylation and methylation by immunohistochemistry. AECs were subjected to chromatin immunoprecipitation (ChIP) using anti-H3K18ac and anti-H3K4me2 antibodies followed by RT-PCR targeting dNp63, EGFR, and STAT6. AECs were also treated with TSA and changes in dNp63, EGFR, and STAT6 expression were determined. Results: We identified an increase in the acetylation of lysine 18 on histone 3 (H3K18ac) and trimethylation of lysine 9 on histone 3 (H3K9me3) in the airway epithelium of asthmatic compared to healthy subjects. We found increased association of H3K18ac around the transcription start site of dNp63, EGFR, and STAT6 in AECs of asthmatics. However, we were unable to modify the expression of these genes with the use of the HDAC inhibitor TSA in healthy subjects. Discussion: The airway epithelium from asthmatic subjects displays increased acetylation of H3K18 and association of this mark around the transcription start site of dNp63, EGFR, and STAT6. These findings suggest a complex interaction between histone modifications and gene regulation in asthma.
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2015 |
Garratt LW, Sutanto EN, Ling KM, Looi K, Iosifidis T, Martinovich KM, et al., 'Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis', European Respiratory Journal, 46 384-394 (2015) [C1] Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is no... [more] Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis. Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active/pro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis. A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of samples. Ratio of active/pro-enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis. Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease.
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2015 |
Hirota JA, Gold MJ, Hiebert PR, Parkinson LG, Wee T, Smith D, et al., 'The Nucleotide-Binding Domain, Leucine-Rich Repeat Protein 3 Inflammasome/IL-1 Receptor I Axis Mediates Innate, but Not Adaptive, Immune Responses after Exposure to Particulate Matter under 10 mu m', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 52 96-105 (2015) [C1]
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2014 |
Murray LA, Zhang H, Oak SR, Coelho AL, Herath A, Flaherty KR, et al., 'Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 50 985-994 (2014) [C1]
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2014 |
Hallstrand TS, Hackett TL, Altemeier WA, Matute-Bello G, Hansbro PM, Knight DA, 'Airway epithelial regulation of pulmonary immune homeostasis and inflammation', Clinical Immunology, 151 1-15 (2014) [C1] Recent genetic, structural and functional studies have identified the airway and lung epithelium as a key orchestrator of the immune response. Further, there is now strong evidenc... [more] Recent genetic, structural and functional studies have identified the airway and lung epithelium as a key orchestrator of the immune response. Further, there is now strong evidence that epithelium dysfunction is involved in the development of inflammatory disorders of the lung. Here we review the characteristic immune responses that are orchestrated by the epithelium in response to diverse triggers such as pollutants, cigarette smoke, bacterial peptides, and viruses. We focus in part on the role of epithelium-derived interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), as well as CC family chemokines as critical regulators of the immune response. We cite examples of the function of the epithelium in host defense and the role of epithelium dysfunction in the development of inflammatory diseases. © 2013 Elsevier Inc.
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2014 |
Hirota JA, Alexis NE, Pui M, Wong S, Fung E, Hansbro P, et al., 'PM10-stimulated airway epithelial cells activate primary human dendritic cells independent of uric acid: Application of an in vitro model system exposing dendritic cells to airway epithelial cell-conditioned media', Respirology, 19 881-890 (2014) [C1] Background and objective Airway epithelial cells represent the first line of defence against inhaled insults, including air pollution. Air pollution can activate innate immune sig... [more] Background and objective Airway epithelial cells represent the first line of defence against inhaled insults, including air pollution. Air pollution can activate innate immune signalling in airway epithelial cells leading to the production of soluble mediators that can influence downstream inflammatory cells. Our objective was to develop and validate a model of dendritic cell exposure to airway epithelial cell-conditioned media. After establishing the model, we explored how soluble mediators released from airway epithelial cells in response to air pollution influenced the phenotype of dendritic cells. Methods Human airway epithelial cells were cultured under control and urban particulate matter (PM10) exposure conditions with or without pharmacological inhibitors of the uric acid pathway. Culture supernatants were collected for conditioned media experiments with peripheral blood mononuclear cell-derived dendritic cells analysed by flow cytometry. Results Monocytes derived from peripheral blood mononuclear cells cultured in interleukin-4 and granulocyte macrophage colony stimulating factor differentiated into immature dendritic cells that phenotypically differentiated into mature dendritic cells in response to conditioned media from phorbol myristate acetate-activated THP-1 monocytes. Exposure of immature dendritic cells to conditioned media from airway epithelial cells exposed to PM10 resulted in dendritic cell maturation that was independent of uric acid. Conclusions We present a conditioned media model useful for interrogating the contribution of soluble mediators produced by airway epithelial cells to dendritic cell phenotype and function. Furthermore, we demonstrate that PM10 exposure induces airway epithelial cell production of soluble mediators that induce maturation of dendritic cells independent of uric acid. We developed and validated a model of airway epithelial cell conditioned media exposure to primary human dendritic cells. Using this model, we then tested the hypothesis that urban particulate matter exposure to airway epithelial cells resulted in production of soluble mediators capable of inducing dendritic cell maturation. © 2014 Asian Pacific Society of Respirology.
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2013 |
Christenson SA, Brandsma C-A, Campbell JD, Knight DA, Pechkovsky DV, Hogg JC, et al., 'MiR-638 regulates gene expression networks associated with emphysematous lung destruction', Genome Medicine, 5 (2013) [C1]
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2013 |
Hirota JA, Hiebert PR, Gold M, Wu D, Graydon C, Smith JA, et al., 'Granzyme B Deficiency Exacerbates Lung Inflammation in Mice after Acute Lung Injury', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 49 453-462 (2013) [C1]
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2013 |
Warner SMB, Hackett T-L, Shaheen F, Hallstrand TS, Kicic A, Stick SM, Knight DA, 'Transcription Factor p63 Regulates Key Genes and Wound Repair in Human Airway Epithelial Basal Cells', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 49 978-988 (2013) [C1]
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2013 |
Hansbro PM, Knight DA, 'Are Lymphoid Follicles Important in the Pathogenesis of Chronic Obstructive Pulmonary Disease?', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 188 267-269 (2013) [C3]
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2013 |
Cruz-Sanchez TM, Haddrell AE, Hackett TL, Singhera GK, Marchant D, Lekivetz R, et al., 'Formation of a Stable Mimic of Ambient Particulate Matter Containing Viable Infectious Respiratory Syncytial Virus and Its Dry-Deposition Directly onto Cell Cultures', ANALYTICAL CHEMISTRY, 85 898-906 (2013) [C1]
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2013 |
Murray LA, Knight DA, 'Advances in industry for chronic respiratory diseases', Inflammation and Allergy - Drug Targets, 12 79-80 (2013) [C3]
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2005 |
O Donoghue RJJ, Anderson GP, Bozinovski S, Jones J, Ernst M, Knight DA, Mutsaers SE, 'Directed Gp130-Mediated Signaling Dissociates Inflammation from Fibrosis in Bleomycin Induced Lung Injury', Inflammation Research, 54 S215-S216 (2005)
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Review (15 outputs)
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2012 |
Roth HM, Wadsworth SJ, Kahn M, Knight DA, 'The airway epithelium in asthma: Developmental issues that scar the airways for life?', Pulmonary Pharmacology and Therapeutics (2012) [D1]
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2012 |
Knight D, Yang IA, Ko FWS, Lim TK, 'Year in review 2011: Asthma, chronic obstructive pulmonary disease and airway biology', Respirology (2012) [D1]
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2011 |
Hirota JA, Hackett T-L, Inman MD, Knight D, 'Modeling asthma in mice: What have we learned about the airway epithelium?', American Journal of Respiratory Cell and Molecular Biology (2011) [D1]
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Show 12 more reviews |
Conference (77 outputs)
Year | Citation | Altmetrics | Link | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
2020 |
Goggins B, Minahan K, Sherwin S, Liu G, Walker M, Horvat J, et al., 'Hypoxia Inducible Factor (HIF)-1 accelerates mucosal wound healing through regulation and trafficking of integrin-alpha 5 beta 1', FASEB JOURNAL, San Diego, CA (2020)
|
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2020 |
Wei L, Read J, Reid AT, Bartlett NW, Grainge C, Knight DA, 'Intrinsic Asthma and Type-2 Cytokines Mediated STAT1 Response to Rhinovirus in Bronchial Epithelial Cells', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, ELECTR NETWORK (2020)
|
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2020 |
Kanwal A, Grainge C, Knight DA, Schuliga M, Bartlett NW, 'The Fibrogenic Actions of IL-25 and Its Potential Role in Idiopathic Pulmonary Fibrosis (IPF)', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, ELECTR NETWORK (2020)
|
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2017 | Shahangian K, Chen H, Ngan DA, Oh Y, Hirota JA, Knight D, et al., 'Infection With Pandemic H1n1 Induces A Dysregulated Il-33 Response In Murine Lungs', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Washington, DC (2017) | ||||||||||
2016 | Chen HR, Ngan DA, Oh Y, Knight DA, Hackett T-L, Dorscheid DR, et al., 'Novel Insights Into The H1n1 Pandemic: Mice Sensitized With House Dust Mite Extract Demonstrate Increased Morbidity From H1n1 Infection', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, San Francisco, CA (2016) | ||||||||||
2015 |
Jones B, Jarnicki A, Smithers N, Knight D, Wark P, Adcock I, Hansbro P, 'EPIGENETIC CHANGES IN HATS AND HDACS DRIVE PATHOGENESIS THAT CAN BE REVERSED USING BET INHIBITORS IN EXPERIMENTAL COPD', RESPIROLOGY, Queensland, AUSTRALIA (2015) [E3]
|
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2015 |
Moheimani F, Roth H, Cross J, Reid A, Shaheen F, Warner S, et al., 'SUPPRESSION OF beta-CATENIN/CBP SIGNALING INHIBITS EPITHELIAL-MESENCHYMAL TRANSITION AND MIGRATION OF HUMAN AIRWAY EPITHELIUM', RESPIROLOGY, Queensland, AUSTRALIA (2015) [E3]
|
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2015 |
Jones B, Jarnicki AG, Smithers N, Knight DA, Wark PA, Adcock IM, Hansbro PM, 'Epigenetic Changes In Hats And Hdacs Drive Pathogenesis That Can Be Reversed Using Bet Inhibitors In Experimental COPD', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Denver, CO (2015)
|
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2015 |
Hansbro P, Haw T, Nair P, Hanish I, Nguyen D, Liu G, et al., 'Tumour necrosis factor-related apoptosis inducing ligand promotes the development of experimental chronic obstructive pulmonary disease', JOURNAL OF IMMUNOLOGY, New Orleans, LA (2015)
|
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2015 | Martinovich K, Iosifidis T, Ling K, Sutanto E, Kicic-Starcevich E, Looi K, et al., 'CONDITIONALLY REPROGRAMMED PRIMARY AIRWAY EPITHELIAL CELLS SUCCESSFULLY MAINTAIN LINEAGE, PHENOTYPIC AND FUNCTIONAL CHARACTERISTICS', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Looi K, Buckley A, Rigby P, Garratt L, Iosifidis T, Lannigan F, et al., 'DISASSEMBLY OF EPITHELIAL TIGHT JUNCTIONS IN WELL-DIFFERENTIATED AIR-LIQUID INTERFACE (ALI) CULTURES FOLLOWING HUMAN RHINOVIRUS INFECTION RESULTS IN AIRWAY EPITHELIAL PERMEABILITY CHANGES', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Iosifidis T, Buckley A, Sutanto E, Ling K, Garratt L, Looi K, et al., 'INVESTIGATION OF MIGRATION MARKERS IN LEADING EDGE CELLS DURING AIRWAY WOUND REPAIR', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Iosifidis T, Sutanto E, Ling K, Garratt L, Looi K, Kicic-Starcevich E, et al., 'ESTABLISHING MIGRATION TRAJECTORIES OF PRIMARY AIRWAY EPITHELIAL CELLS DURING WOUND REPAIR', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Sohal S, Mahmood M, Shukla S, Hardikar A, Noor W, Muller H, et al., 'EPITHELIAL MESENCHYMAL TRANSITION (EMT) IN SMOKERS: LARGE VERSUS SMALL AIRWAYS; AND RELATION TO AIRFLOW OBSTRUCTION', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Larcombe A, Janka M, Looi K, Rigby P, Knight D, Berry L, et al., 'INFLUENZA INFECTION FACILITATES ALLERGEN-SPECIFIC RESPONSES IN PRE-SENSITIZED MICE', RESPIROLOGY (2015) [E3] | ||||||||||
2015 | Garratt LW, Sutanto EN, Ling K, Looi K, Iosifidis T, Martinovich KM, et al., 'DEFINING PROTEASE INHIBITION OF AIRWAY EPITHELIAL CELL FUNCTION FOR ASSESSMENT OF ANTI-PROTEASE THERAPY', PEDIATRIC PULMONOLOGY (2015) [E3] | ||||||||||
2015 | Chen HR, Ngan DA, Oh Y, Hirota JA, Knight DA, Hackett T-L, et al., 'Mice Sensitized With House Dust Mite Extract Had Greater Weight Loss And Viral Load Following H1n1 Infection', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Denver, CO (2015) | ||||||||||
2014 |
Goggins B, Minahan K, Marks E, Mateer S, Cardona J, Knight D, et al., 'Hypoxia inducible factor (HIF)-1 accelerates epithelial wound healing through integrin regulation', JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY (2014) [E3]
|
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2014 |
Starkey M, Hanish I, Dua K, Nair P, Haw T, Hsu A, et al., 'Interleukin-13 predisposes mice to more severe influenza infection by suppressing interferon responses and activating microRNA-21/PI3K', CYTOKINE, Melbourne, AUSTRALIA (2014) [E3]
|
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2014 | Garratt LW, Sutanto EN, Ling KM, Looi K, Kicic-Starcevich E, Iosifidis T, et al., 'IDENTIFICATION OF MMP DYSREGULATION IN EARLY CF - EVIDENCE BASED RATIONALE FOR ANTI-PROTEASE THERAPY', RESPIROLOGY (2014) [E3] | ||||||||||
2014 | Prele C, Handoko A, Lau H, O'Donoghue R, Mcanulty R, Laurent G, et al., 'MECHANISMS UNDERLYING STAT3-INDUCED LUNG FIBROSIS', RESPIROLOGY (2014) | ||||||||||
2014 | Warner S, Gower A, Liu G, Sin D, Hallstrand TS, Spira A, et al., 'Distinct Epithelial Mrna And Mirna Expression Profiles During Differentiation And Between Eib plus And Eib- Asthma Phenotypes', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014) | ||||||||||
2014 | Ghavami S, Yeganeh B, Zeki AA, Kenyon NJ, Ott S, Chan A, et al., 'Autophagy And The Unfolded Protein Response Are Necessary For Tgf beta 1-Induced Profibrotic Effects In Normal And Idiopathic Pulmonary Fibrosis Fibroblasts', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014) | ||||||||||
2014 |
Starkey MR, Hanish I, Dua K, Hsu A, Monogar P, Foster PS, et al., 'Interleukin-13 Predisposes Mice To More Severe Influenza Infection And Exacerbated Allergic Airways Disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014)
|
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2014 |
Hirota JA, Gold MJ, Hiebert P, Le A, Park H, Stefanowicz D, et al., 'Identification Of A Novel Uric Acid Transport System In Human Airway Epithelial Cells That Contributes To Innate And Adaptive Immune Responses', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014)
|
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2013 | Looi K, Larcombe A, Zosky G, Rigby P, Knight DA, Stick SM, Kicic A, 'HUMAN RHINOVIRUS INFECTION INITIATES AIRWAY EPITHELIAL TIGHT JUNCTION DISASSEMBLY RESULTING IN BARRIER FUNCTION DISRUPTION', RESPIROLOGY (2013) [E3] | ||||||||||
2013 |
Looi K, Larcombe A, Zosky G, Rigby P, Knight DA, Stick SM, Kicic A, 'HUMAN RHINOVIRUS INFECTION OF ASTHMATIC AIRWAY EPITHELIAL CELLS CAUSES TIGHT JUNCTION DISASSEMBLY RESULTING IN INCREASED PERMEABILITY', RESPIROLOGY (2013) [E3]
|
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Show 74 more conferences |
Grants and Funding
Summary
Number of grants | 67 |
---|---|
Total funding | $13,180,817 |
Click on a grant title below to expand the full details for that specific grant.
20231 grants / $597,680
The roles of replicative senescence and telomere dysfunction in the heightened injury and disrepair responses of alveolar epithelial cells from patients with pulmonary fibrosis$597,680
Funding body: Boehringer Ingelheim Pharma GmbH & Co KG
Funding body | Boehringer Ingelheim Pharma GmbH & Co KG |
---|---|
Project Team | Doctor Michael Schuliga, Conjoint Associate Professor Christopher Grainge, Professor Darryl Knight |
Scheme | Research Grant |
Role | Investigator |
Funding Start | 2023 |
Funding Finish | 2025 |
GNo | G2301207 |
Type Of Funding | C3400 – International For Profit |
Category | 3400 |
UON | Y |
20211 grants / $469,688
To Support The Potential Identification Of New Therapeutic Targets In IPF/PF-ILD Patient-Derived Airway And Alveolar Epithelial Cell Cultures$469,688
Funding body: Boehringer Ingelheim Pharma GmbH & Co KG
Funding body | Boehringer Ingelheim Pharma GmbH & Co KG |
---|---|
Project Team | Doctor Michael Schuliga, Professor Darryl Knight |
Scheme | Research Grant |
Role | Investigator |
Funding Start | 2021 |
Funding Finish | 2023 |
GNo | G2100417 |
Type Of Funding | C3400 – International For Profit |
Category | 3400 |
UON | Y |
20182 grants / $1,109,379
How does bronchoconstriction worsen asthma? $1,104,379
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Conjoint Associate Professor Christopher Grainge, Professor Nathan Bartlett, Professor Darryl Knight, Conjoint Professor Peter Wark, Professor Alastair Stewart, Stewart, Alastair |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2018 |
Funding Finish | 2021 |
GNo | G1700343 |
Type Of Funding | C1100 - Aust Competitive - NHMRC |
Category | 1100 |
UON | Y |
Annexin A2 in IPF and potential as novel therapeutic target$5,000
Funding body: Lung Foundation Australia
Funding body | Lung Foundation Australia |
---|---|
Project Team | Doctor Michael Schuliga, Professor Darryl Knight, Conjoint Associate Professor Christopher Grainge |
Scheme | Lizotte Family Research Award for Interstitial Pulmonary Fibrosis Research |
Role | Investigator |
Funding Start | 2018 |
Funding Finish | 2018 |
GNo | G1801058 |
Type Of Funding | C3200 – Aust Not-for Profit |
Category | 3200 |
UON | Y |
20173 grants / $164,128
Novel epithelial targets and targeting strategies to prevent asthma exacerbations$136,364
Funding body: Asthma Australia
Funding body | Asthma Australia |
---|---|
Project Team | Professor Nathan Bartlett, Conjoint Professor Peter Wark, Doctor Roger Liang, Professor Darryl Knight |
Scheme | National Research Program |
Role | Investigator |
Funding Start | 2017 |
Funding Finish | 2018 |
GNo | G1601217 |
Type Of Funding | C3100 – Aust For Profit |
Category | 3100 |
UON | Y |
Mechano-transduction signaling complexes of urokinase and its receptor in lung fibrosis: A potential target for idiopathic pulmonary fibrosis (IPF)$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Michael Schuliga, Conjoint Associate Professor Christopher Grainge, Professor Darryl Knight |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2017 |
Funding Finish | 2017 |
GNo | G1700697 |
Type Of Funding | C3200 – Aust Not-for Profit |
Category | 3200 |
UON | Y |
Development of a medium throughput assay for assessing compounds that modulate fibroblast function in COPD$7,764
Funding body: Metera Pharmaceuticals Inc
Funding body | Metera Pharmaceuticals Inc |
---|---|
Project Team | Professor Darryl Knight, Dr Michael Schuliga, Doctor Andrew Reid |
Scheme | Research Consultancy |
Role | Lead |
Funding Start | 2017 |
Funding Finish | 2017 |
GNo | G1701512 |
Type Of Funding | C3500 – International Not-for profit |
Category | 3500 |
UON | Y |
20166 grants / $1,791,378
Fibroblast Senescence as a driver of pulmonary fibrosis$873,216
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Darryl Knight, Associate Professor Janette Burgess, Associate Professor Glen Westall, Professor Geoffrey Laurent, Dr Cecilia Prele, Associate Professor Steven Mutsaers |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2016 |
Funding Finish | 2019 |
GNo | G1500128 |
Type Of Funding | C1100 - Aust Competitive - NHMRC |
Category | 1100 |
UON | Y |
Collaborative Research Agreement: New pathways and targets in severe asthma and COPD$611,171
Funding body: Boehringer Ingelheim Pharma GmbH & Co KG
Funding body | Boehringer Ingelheim Pharma GmbH & Co KG |
---|---|
Project Team | Professor Darryl Knight, Conjoint Associate Professor Christopher Grainge, Conjoint Professor Peter Wark, Professor Nathan Bartlett |
Scheme | Research Grant |
Role | Lead |
Funding Start | 2016 |
Funding Finish | 2019 |
GNo | G1601257 |
Type Of Funding | C3400 – International For Profit |
Category | 3400 |
UON | Y |
Centre for Research Excellence in Pulmonary Fibrosis$221,991
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Tamera Corte, Professor Darryl Knight, Professor Geoffrey Laurent, Professor Anne Holland, Associate Professor Daniel Chambers, Associate Professor Yuben Moodley, Professor Eugene Walters, Associate Professor Glen Westall, Associate Professor Ian Glaspole, Professor Andrew Palmer |
Scheme | Centres of Research Excellence - Centres of Clinical Research Excellence (CRE) |
Role | Lead |
Funding Start | 2016 |
Funding Finish | 2021 |
GNo | G1700420 |
Type Of Funding | C1100 - Aust Competitive - NHMRC |
Category | 1100 |
UON | Y |
Fibroblast senescence as a driver of Pulmonary Fibrosis$45,000
Funding body: Lung Foundation Australia
Funding body | Lung Foundation Australia |
---|---|
Project Team | Mr David Waters, Professor Darryl Knight |
Scheme | David Wilson PhD Scholarship in Idiopathic Pulmonary Fibrosis |
Role | Lead |
Funding Start | 2016 |
Funding Finish | 2018 |
GNo | G1601072 |
Type Of Funding | C3200 – Aust Not-for Profit |
Category | 3200 |
UON | Y |
Emlyn and Jennie Thomas Postgraduate Medical Research Scholarship$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Miss Bridie Goggins, Professor Simon Keely, Professor Darryl Knight, Professor Jay Horvat |
Scheme | Postgraduate Research Scholarship |
Role | Investigator |
Funding Start | 2016 |
Funding Finish | 2017 |
GNo | G1600721 |
Type Of Funding | C3300 – Aust Philanthropy |
Category | 3300 |
UON | Y |
A novel approach in restoring the airway epithelium integrity in asthmatics$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Fatemeh Moheimani, Professor Darryl Knight |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2016 |
Funding Finish | 2016 |
GNo | G1600919 |
Type Of Funding | C3300 – Aust Philanthropy |
Category | 3300 |
UON | Y |
20154 grants / $1,029,448
Modifying epigenetics as a novel treatment in COPD$902,888
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Phil Hansbro, Professor Darryl Knight, Conjoint Professor Peter Wark, Prof Ian Adcock |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2015 |
Funding Finish | 2019 |
GNo | G1400006 |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | Y |
Modifying epigenetics as a novel treatment in COPD$76,338
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Darryl Knight, Professor Darryl Knight, Professor Phil Hansbro, Professor Philip Hansbro, Conjoint Professor Peter Wark, Prof Ian Adcock |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2015 |
Funding Finish | 2020 |
GNo | G1900807 |
Type Of Funding | C1100 - Aust Competitive - NHMRC |
Category | 1100 |
UON | Y |
Do viral infection and bronchoconstriction interact during exacerbation of asthma prolonging viral infection and worsening disease in the long term?$25,222
Funding body: John Hunter Hospital Charitable Trust
Funding body | John Hunter Hospital Charitable Trust |
---|---|
Project Team | Conjoint Associate Professor Christopher Grainge, Professor Darryl Knight |
Scheme | Research Grant |
Role | Investigator |
Funding Start | 2015 |
Funding Finish | 2015 |
GNo | G1500546 |
Type Of Funding | Other Public Sector - State |
Category | 2OPS |
UON | Y |
Specifically targeting the airways to prevent virus-induced asthma attacks$25,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Professor Nathan Bartlett, Professor Darryl Knight |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2015 |
Funding Finish | 2016 |
GNo | G1501378 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
20147 grants / $848,306
A novel approach to understanding Asthma: Focus on the epithelium $633,228
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Darryl Knight, Professor Phil Hansbro, Professor Stephen Stick, Dr Anthony Kicic |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2017 |
GNo | G1300212 |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | Y |
The Nanostring nCounter System$75,000
Funding body: Ramaciotti Foundations
Funding body | Ramaciotti Foundations |
---|---|
Project Team | Professor Darryl Knight, Professor Phil Hansbro, Professor Paul Foster, Professor Rodney Scott, Conjoint Professor Peter Gibson, Professor Michael Nilsson |
Scheme | Major Equipment Award |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1300853 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
The Nanostring nCounter System$40,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Professor Darryl Knight, Professor Phil Hansbro, Professor Paul Foster, Professor Rodney Scott, Conjoint Professor Peter Gibson, Professor Michael Nilsson |
Scheme | Equipment Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1301083 |
Type Of Funding | Other Public Sector - State |
Category | 2OPS |
UON | Y |
Do asthma attacks worsen asthma in the long term?$29,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Conjoint Associate Professor Christopher Grainge, Professor Darryl Knight |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2015 |
GNo | G1401402 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
Mechanisms of dysregulated antiviral signallings to influenza infection in chronic obstructive pulmonary disease$27,512
Funding body: John Hunter Hospital Charitable Trust
Funding body | John Hunter Hospital Charitable Trust |
---|---|
Project Team | Doctor Alan Hsu, Doctor Fatemeh Moheimani, Professor Darryl Knight, Conjoint Professor Peter Wark |
Scheme | Research Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1400435 |
Type Of Funding | Other Public Sector - State |
Category | 2OPS |
UON | Y |
Miltenyi Biotec GentleMACS Octo Dissociator with Heaters $23,566
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Phil Hansbro, Professor Paul Foster, Professor Darryl Knight, Professor Dirk Van Helden, Professor Joerg Mattes, Professor Jodie Simpson, Professor Lisa Wood, Prof LIZ Milward, Dr NATHAN Bartlett, Professor Simon Keely, Doctor Steven Maltby, Doctor Andrew Jarnicki, Doctor Malcolm Starkey, Associate Professor Adam Collison, Doctor Shaan Gellatly |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1500861 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
The Nanostring nCounter System$20,000
Funding body: John Hunter Hospital Charitable Trust
Funding body | John Hunter Hospital Charitable Trust |
---|---|
Project Team | Professor Darryl Knight, Professor Phil Hansbro, Professor Paul Foster, Professor Rodney Scott, Conjoint Professor Peter Gibson, Professor Michael Nilsson |
Scheme | Research Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1301084 |
Type Of Funding | Other Public Sector - State |
Category | 2OPS |
UON | Y |
20132 grants / $605,430
Defective cell migration as a mechanism of dysregulated asthmatic airway repair$595,430
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Doctor Anthony Kicic |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2013 |
Funding Finish | 2015 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Role of the transcriptional co-activator p300 in resetting epithelial differentiation: A potential pathway involved in asthma prevention and therapy$10,000
Funding body: University of Newcastle
Funding body | University of Newcastle |
---|---|
Project Team | Doctor Fatemeh Moheimani, Professor Darryl Knight, Ms Kirsty Wark, Doctor Alan Hsu, Doctor Malcolm Starkey |
Scheme | Early Career Researcher Grant |
Role | Investigator |
Funding Start | 2013 |
Funding Finish | 2013 |
GNo | G1301174 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20121 grants / $510,000
Airway epithelial barrier function, asthma and aero?allergen sensitization.$510,000
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Prof Stephen Stick |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2012 |
Funding Finish | 2014 |
GNo | |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | N |
20113 grants / $258,465
Inhaled Corticosteroids as risk factors for severe viral infections in asthmatics: lessons from the H1N1 epidemic$130,558
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | Donald Sin |
Scheme | Operating Grant |
Role | Investigator |
Funding Start | 2011 |
Funding Finish | 2013 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Resetting epithelial differentiation as a novel therapeutic approach to treating asthma$120,407
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Operating Grant |
Role | Lead |
Funding Start | 2011 |
Funding Finish | 2013 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Heart and Lung Health FEST 2011$7,500
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Meetings, Planning and Dissemination Grant: Circulatory and Respiratory Health |
Role | Lead |
Funding Start | 2011 |
Funding Finish | 2011 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20103 grants / $144,155
Exacerbation of H1N1 Influenza infection with inhaled therapeutics in primary epithelial cells and ex vivo tissue from asthma patients: clarification of primary treatment strategies during pandemic in$94,155
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Operating Grant: Health Systems Research on H1N1 |
Role | Lead |
Funding Start | 2010 |
Funding Finish | 2011 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Defining phenotypes of fibroblasts within the human airways and lung parenchyma for better understanding of fibrotic diseases$25,000
Funding body: British Columbia Lung Association
Funding body | British Columbia Lung Association |
---|---|
Project Team | Dmitri Pechkovsky |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2010 |
Funding Finish | 2012 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
New emerging paradigm in asthma: The role of E-cadherin in aberrant airway epithelial repair$25,000
Funding body: British Columbia Lung Association
Funding body | British Columbia Lung Association |
---|---|
Project Team | Tillie-Louise Hackett |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2010 |
Funding Finish | 2012 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20093 grants / $948,449
Dysregulated STAT-3 activation underlies lung fibroblast heterogeneity: Implications for idiopathic pulmonary fibrosis$464,649
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Operating Grant |
Role | Lead |
Funding Start | 2009 |
Funding Finish | 2013 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Canada Research Chairholder$375,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Canada Research Chairs - CIHR Funded - Tier 2 |
Role | Lead |
Funding Start | 2009 |
Funding Finish | 2013 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Regulation of mesenchymal cell behaviour by versican: Implications of arterial remodeling$108,800
Funding body: Heart & Stroke Foundation
Funding body | Heart & Stroke Foundation |
---|---|
Project Team | Bruce McManus |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2009 |
Funding Finish | 2012 |
GNo | |
Type Of Funding | International - Non Competitive |
Category | 3IFB |
UON | N |
20081 grants / $150,000
Novel Therapy for Pulmonary Fibrosis$150,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Proof of Principle Program - Phase I |
Role | Lead |
Funding Start | 2008 |
Funding Finish | 2009 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20073 grants / $664,500
The role of gp130 receptor mediated signalling in fibrotic pulmonary diseases.$544,500
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2007 |
Funding Finish | 2009 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Dysregulated epithelial repair in pediatric asthma$100,000
Funding body: Johnson & Johnson Medical Education Foundation
Funding body | Johnson & Johnson Medical Education Foundation |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2007 |
Funding Finish | 2010 |
GNo | |
Type Of Funding | International - Non Competitive |
Category | 3IFB |
UON | N |
Dysregulated STAT-3 activation in the Pathogenesis of IPF$20,000
Funding body: British Columbia Lung Association
Funding body | British Columbia Lung Association |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2007 |
Funding Finish | 2009 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20062 grants / $713,151
Genetic and epigenetic determinants of asthmatic epithelial cell Phenotype$369,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | Peter Pare |
Scheme | Operating Grant |
Role | Investigator |
Funding Start | 2006 |
Funding Finish | 2010 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Environmental impact on the epithelial immune barrier in asthma$344,151
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | . |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2006 |
Funding Finish | 2008 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20054 grants / $426,750
Regulation of gp130 signaling by STAT-3 in the pathogenesis of pulmonary fibrosis$251,084
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Operating Grant |
Role | Lead |
Funding Start | 2005 |
Funding Finish | 2009 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Role and regulation of the proteoglycan, versican, in vascular injury and repair$110,666
Funding body: Heart & Stroke Foundation
Funding body | Heart & Stroke Foundation |
---|---|
Project Team | Bruce McManus |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2005 |
Funding Finish | 2008 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Regulation of gp130 signaling by STAT-3 in the pathogenesis of pulmonary fibrosis$50,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Operating Grant -PA: Inst of Circulatory and Respiratory Health - Bridge Funding |
Role | Lead |
Funding Start | 2005 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Regulation of gp130 signaling of gp130 in the pathogenesis of pulmonary fibrosis$15,000
Funding body: Providence Health Care
Funding body | Providence Health Care |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2005 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | International - Non Competitive |
Category | 3IFB |
UON | N |
20047 grants / $1,874,836
Canada Research Chairholder$500,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Canada Research Chairs - CIHR Funded - Tier 2 |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2010 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Altered signalling by a common cytokine receptor is important in the development of fibrotic lung diseases.$449,750
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Dr Steven Mutsaers |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Establishment Grant$301,000
Funding body: Canadian Institutes of Health Research
Funding body | Canadian Institutes of Health Research |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Institutional Establishment Grant (IEG) Program |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2004 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
The airway epithelium, atopy and asthma$259,750
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | A/Prof Stephen Stick |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | N |
Role Of Zinc In The Respiratory Epithelium and asthma$220,500
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Dr Peter Zalewski |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Mechanisms of Airway Disease$114,416
Funding body: Canadian Foundation for Innovation
Funding body | Canadian Foundation for Innovation |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Canada Research Chairs Infrastructure Fund |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2004 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
Integrin-growth factor interactions in the development of airway wall remodeling$29,420
Funding body: British Columbia Lung Association
Funding body | British Columbia Lung Association |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2004 |
Funding Finish | 2006 |
GNo | |
Type Of Funding | International - Competitive |
Category | 3IFA |
UON | N |
20034 grants / $509,098
Regulation of the structural changes in the airways of chronic asthmatics$384,000
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2003 |
Funding Finish | 2005 |
GNo | |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | N |
Equipment grant$73,000
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Geoffrey Stewart |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2003 |
Funding Finish | 2003 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Infrastructure grant$36,098
Funding body: Medical and Health Research Infrastructure Council (MHRIC)
Funding body | Medical and Health Research Infrastructure Council (MHRIC) |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Infrastructure grant |
Role | Lead |
Funding Start | 2003 |
Funding Finish | 2003 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
Equipment grant$16,000
Funding body: Rebecca L Cooper Medical Research Foundation Ltd
Funding body | Rebecca L Cooper Medical Research Foundation Ltd |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2003 |
Funding Finish | 2003 |
GNo | |
Type Of Funding | International - Non Competitive |
Category | 3IFB |
UON | N |
20022 grants / $15,000
Three-dimensional confocal analysis of sensory nerves, neuroendocrine cells and dendritic cells in human airways.$10,000
Funding body: Sir Charles Gairdner Hospital
Funding body | Sir Charles Gairdner Hospital |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2002 |
Funding Finish | 2002 |
GNo | |
Type Of Funding | Aust Competitive - Non Commonwealth |
Category | 1NS |
UON | N |
University of Western Australia$5,000
Funding body: University of Western Australia
Funding body | University of Western Australia |
---|---|
Project Team | John Upham |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2002 |
Funding Finish | 2002 |
GNo | |
Type Of Funding | Internal |
Category | INTE |
UON | N |
20012 grants / $105,400
The Immunobiology of Asthma with particular reference to the Respiratory Epithelium$61,500
Funding body: Sir Charles Gairdner Hospital
Funding body | Sir Charles Gairdner Hospital |
---|---|
Project Team | Geoffrey Stewart |
Scheme | Funds Granted |
Role | Investigator |
Funding Start | 2001 |
Funding Finish | 2002 |
GNo | |
Type Of Funding | Aust Competitive - Non Commonwealth |
Category | 1NS |
UON | N |
Interleukin (IL-) 11 and IL-6 differentially influence fibroblast proliferation and apoptosis: Implications for airway inflammation and airway remodeling$43,900
Funding body: Asthma Foundation of Western Australia
Funding body | Asthma Foundation of Western Australia |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 2001 |
Funding Finish | 2001 |
GNo | |
Type Of Funding | Aust Competitive - Non Commonwealth |
Category | 1NS |
UON | N |
20001 grants / $76,700
Epithelium-fibroblast interactions in response to allergic airway inflammation$76,700
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2000 |
Funding Finish | 2002 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
19993 grants / $91,476
The role of Oncostatin M and Leukemia Inhibitory Factor in airway remodeling$48,576
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Project Grant |
Role | Lead |
Funding Start | 1999 |
Funding Finish | 2001 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
The effects of house dust mite allergens on the activation of submucosal glands and mucus secretion in human isolated airways: The modulatory role of Oncostatin M and Leukemia Inhibitory Factor.$22,900
Funding body: Asthma Foundation of Western Australia
Funding body | Asthma Foundation of Western Australia |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 1999 |
Funding Finish | 1999 |
GNo | |
Type Of Funding | Aust Competitive - Non Commonwealth |
Category | 1NS |
UON | N |
Assessment of the effects of chronic inflammation on structural remodelling and functional responses of human airways in vitro.$20,000
Funding body: Lung Foundation Australia
Funding body | Lung Foundation Australia |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Shared |
Role | Lead |
Funding Start | 1999 |
Funding Finish | 2000 |
GNo | |
Type Of Funding | Aust Competitive - Non Commonwealth |
Category | 1NS |
UON | N |
19981 grants / $57,400
A novel explant model to investigate epithelial damage and airway remodelling in human airways. $57,400
Funding body: Raine Medical Research Foundation
Funding body | Raine Medical Research Foundation |
---|---|
Project Team | A/Prof Darryl Knight |
Scheme | Funds Granted |
Role | Lead |
Funding Start | 1998 |
Funding Finish | 1999 |
GNo | |
Type Of Funding | Not Known |
Category | UNKN |
UON | N |
1 grants / $20,000
Immunosenescence in chronic obstructive pulmonary disease leads to abnormal innate immune responses to human rhinovirus infection$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Conjoint Professor Peter Wark, Professor Darryl Knight |
Scheme | Project Grant |
Role | Investigator |
Funding Start | |
Funding Finish | |
GNo | G1301331 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
Research Supervision
Number of supervisions
Current Supervision
Commenced | Level of Study | Research Title | Program | Supervisor Type |
---|---|---|---|---|
2022 | PhD | The Role Of Epithelial Senescence In Lung Injury And Fibrosis | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2017 | PhD | Extracellular DNA (eDNA) in Pleural Fluid as a Determinant of Pathology and Treatment Response | PhD (Medicine), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2017 | PhD | An Investigation of Regional Heterogeneity of the Pulmonary Microenvironment in Idiopathic Pulmonary Fibrosis | PhD (Medicine), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
Past Supervision
Year | Level of Study | Research Title | Program | Supervisor Type |
---|---|---|---|---|
2022 | PhD | The Role of STATs in the Interaction of Virus and Type 2 Cytokines in Airway Epithelial Cells | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | The Impact of Respiratory Virus Infection on Airway Epithelial Cell Differentiation and Barrier Formation in Asthma | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | Development of Airway Epithelial Targeted Nanoparticles Loaded with TLR7 agonist for Asthma Therapy | PhD (Pharmacy), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | The Interplay between Epithelial-derived Type-2 Inflammation and Rhinovirus Infection in Asthma | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | The ECM as a Driver of Fibroblast Senescence and Disrupted Epithelial Repair in IPF | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2021 | PhD | The Role of E-Cadherin/¿-Catenin Signalling in the Development of an Asthmatic Airway Epithelial Phenotype | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2020 | PhD | Rhinovirus Diversity and Replication in Differentiated Airway Epithelial Cells | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2020 | PhD | The Roles of Mast Cells and Mast Cell Proteases During Chlamydia Reproductive Tract Infection | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2019 | PhD | Fibroblast Senescence as a Driver of Idiopathic Pulmonary Fibrosis | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2019 | PhD | In Vitro And in Vivo Investigations of the a-Integrins Regulated by Hypoxia Inducible Factor (HIF)-1 Signalling during Mucosal Wound Healing | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2019 | PhD | Contribution of Cell Death to the Pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2019 | PhD | Deep Time-Resolved Proteomic and Phosphoproteomic Profiling of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease | PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2019 | PhD | Role of Mechanical Forces in Asthma Pathogenesis | PhD (Medicine), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2011 | Post-Doctoral Fellowship | Regulation of epithelial cell differentiation | Health, University of British Columbia | Principal Supervisor |
2011 | Masters | Role of STAT-3 in regulating fibroblast function | Health, University of British Columbia | Principal Supervisor |
2009 | PhD | Characterising factors that regulate epithelial proliferation in childhood asthma | Health, University of Western Australia | Principal Supervisor |
2008 | PhD | Role of Gp130/STAT-3 in pulmonary fibrosis | Health, University of Western Australia | Principal Supervisor |
2007 | Post-Doctoral Fellowship | HB-EGF, TGF? and epithelial function | Health, University of British Columbia | Principal Supervisor |
2007 | PhD | Airway epithelium and particular matter air pollutuion | Health, University of Western Australia | Co-Supervisor |
2006 | PhD | Paediatric airway epithelial cells in asthma | Health, University of Western Australia | Co-Supervisor |
2006 | PhD | Characterising the role of oncostatin M in human lung | Health, University of Western Australia | Principal Supervisor |
2005 | PhD | Interaction between integrins and growth factors of fibroblast function | Health, University of Western Australia | Principal Supervisor |
2004 | PhD | Gp130/STAT3 activation in pulmonary fibrosis | Health, University of Western Australia | Principal Supervisor |
2003 | Post-Doctoral Fellowship | Integrins and epithelial function | Health, University of Western Australia | Principal Supervisor |
2003 | Honours | Integrins and growth Factors and epithelial cells | Health, University of Western Australia | Principal Supervisor |
2002 | Honours | Interaction between viruses and oncostatin M in human airway epithelium | Health, University of Western Australia | Principal Supervisor |
Research Collaborations
The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.
Country | Count of Publications | |
---|---|---|
Australia | 234 | |
Canada | 182 | |
United States | 96 | |
United Kingdom | 42 | |
Netherlands | 41 | |
More... |
News
News • 10 Nov 2015
NHMRC funding success 2016
Professor Darryl Knight has been awarded more than $845,000 in NHMRC Project Grant funding commencing in 2016 for his research project Fibroblast Senescence as a driver of pulmonary fibrosis.
Professor Darryl Knight
Position
Honorary Professor
School of Biomedical Sciences and Pharmacy
College of Health, Medicine and Wellbeing
Contact Details
darryl.knight@newcastle.edu.au |