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Dr Doug Smith

Senior Lecturer

School of Biomedical Sciences and Pharmacy (Anatomy)

Career Summary

Biography

Eleven peer-reviewed research publications from PhD studies Awarded CJ Martin fellowship Complete change in direction of research to acquire state-of-the-art techniques in USA Returned to Australia and established single-cell genomics capability Establishing new research program into the effects of aging on brain function. Establishing collaborations with groups studying addiction and depression

Research Expertise
The main aim of my lab's research is to better understand the effects of ageing on nervous system function. It is well known that the world's population is ageing and soon there will be more people over the age of 65 than there are children. If we are to improve the quality of life of the aged, then we must first understand how ageing affects the body's various physiological systems. As the nervous system has an important role in most functions, its preservation with ageing is paramount.

We are primarily using molecular approaches and focusing on ageing-related changes in the cell's two genomes - the nuclear and mitochondrial genomes. It is well-established that both genomes accumulate mutations with ageing, although it is not completely clear whether these mutations are more detrimental to cell function if they accumulate more so in one of the genomes as opposed to the other. It is also not known whether the mutation accumulations occur in a cell-specific manner. This is particularly important for the nervous system with its highly heterogeneous cell population. A number of nervous system functions appear more susceptible to the ageing process than others. For example, the special senses of hearing, vision and balance are particularly prone, although it remains to be determined whether the peripheral components of these systems (cochlea, retina, and vestibular apparatus, respectively) are more affected than their central nervous system connections and processes.

Cognitive function and motor control are two more nervous system functions that are affected by the ageing process as can be readily observed in the aged population. We are characterising the genomic changes in specific populations of cells within these ageing-affected systems. For example, using state-of-the-art, laser based microdissection, we can collect midbrain dopamine neurons, which play an important role in motor control as can be appreciated from Parkinson's disease, at different ages and determine changes in mitochondrial DNA and the expression level of various genes.

Similar approaches are being used for spinal cord motor neurons and inner ear vestibular hair cells. Knowing how ageing affects the nervous system is important, but we also need to be able to intervene if we are to improve the quality of life of aged individuals. Calorie restriction, whereby the daily calorie intake is reduced by 20-40% (but without malnutrition), is the only presently known intervention that retards the ageing process, at least in animal models. We are establishing CR to determine whether the ageing-related changes we see in the various cell populations of interest are modified by this intervention. If this is the case, we will then set out to determine how CR achieves this.

Research methods used in the lab include: Animal models Laser based microdissection Immunocytochemistry RNA and DNA techniques Real-time and end-point PCR Immunofluorescence microscopy Cryosectioning


Qualifications

  • Doctor of Philosophy, University of Queensland

Keywords

  • Aging and Brain Function
  • Anatomy
  • Animal Models
  • Cell Culture Models
  • Developmental Neurobiology
  • Ergonomics
  • Gene Expression
  • Immunocytochemistry
  • Mitochondrial genomics
  • Modern Techniques
  • Molecular Biology
  • Neuroanatomy
  • Neurobiology
  • Physiology
  • Single Cell Genomics
  • Viral Vectors

Fields of Research

Code Description Percentage
060199 Biochemistry and Cell Biology not elsewhere classified 25
110399 Clinical Sciences not elsewhere classified 50
170199 Psychology not elsewhere classified 25

Professional Experience

UON Appointment

Title Organisation / Department
Senior Lecturer University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Academic appointment

Dates Title Organisation / Department
1/03/2005 - 21/06/2015 Academic University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia
1/07/1997 - 1/04/2004 Research Scientist University of California, San Diego
Department of Pediatrics, School of Medicine UCSD
United States

Awards

Research Award

Year Award
1995 CJ Martin Fellowship
Unknown
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Journal article (37 outputs)

Year Citation Altmetrics Link
2015 McIlroy DJ, Bigland M, White AE, Hardy BM, Lott N, Smith DW, Balogh ZJ, 'Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery', Journal of Trauma and Acute Care Surgery, 78 282-288 (2015)

Background: Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on ... [more]

Background: Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on mtDNA concentration is unknown. We hypothesized that mtDNA and nuclear DNA (nDNA) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly. Methods: In this prospective pilot, plasma was sampled from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points. Healthy control subjects (n = 20)were sampled.DNAwas extracted, and the mtDNA and nDNAwere assessed using quantitative polymerase chain reaction. Markers of cell necrosis were also assayed (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase). Results: The free plasma mtDNA and nDNA levels (ng/mL) were increased in trauma patients compared with healthy controls at all time points (mtDNA: preoperative period, 108 [46-284]; postoperative period, 96 [29-200]; 7 hours postoperatively, 88 [43-178]; 24 hours, 79 [36-172]; 3 days, 136 [65-263]; 5 days, 166 [101-434] [healthy controls, 11 (5-19)]) (nDNA: preoperative period, 52 [25-130]; postoperative period, 100 [35-208]; 7 hours postoperatively, 75 [36-139]; 24 hours postoperatively, 85 [47-133]; 3 days, 79 [48-117]; 5 days, 99 [41-154] [healthy controls, 29 (16-54)]). Elevated DNA levels did not correlate with markers of cellular necrosis. mtDNA was significantly elevated compared with nDNA at preoperative period (p = 0.003), 3 days (p = 0.003), and 5 days (p = 0.0014). Preoperative mtDNA levelswere greater with shorter time from injury to surgery (p = 0.0085). Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion (p = 0.0017). Major pelvic surgery (vs. minor) was associated with greater mtDNA release 5 days postoperatively (p G 0.05). Conclusion: This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery. Postoperative, circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration. Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation. Level of Evidence: Prospective study, level III.

DOI 10.1097/TA.0000000000000519
Citations Scopus - 2Web of Science - 2
Co-authors Zsolt Balogh
2015 McIlroy DJ, Bigland M, White AE, Hardy BM, Lott N, Smith DW, Balogh ZJ, 'Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery.', J Trauma Acute Care Surg, 78 282-288 (2015)
DOI 10.1097/TA.0000000000000519
Citations Web of Science - 2
Co-authors Zsolt Balogh
2014 James MH, Quinn RK, Ong LK, Levi EM, Charnley JL, Smith DW, et al., 'mTORC1 inhibition in the nucleus accumbens 'protects' against the expression of drug seeking and 'relapse' and is associated with reductions in GluA1 AMPAR and CAMKIIa levels.', Neuropsychopharmacology, 39 1694-1702 (2014) [C1]
DOI 10.1038/npp.2014.16
Citations Scopus - 2
Co-authors Christopher Dayas, Phil Dickson, Linkooi Ong
2014 McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, Balogh ZJ, 'Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery', Journal of Critical Care, 29 1133.e1-1133.e5 (2014)
DOI 10.1016/j.jcrc.2014.07.013
Co-authors Philip Hansbro, Zsolt Balogh, Gough Au
2014 McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, Balogh ZJ, 'Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery', Journal of Critical Care, 29 1133.e1-1133.e5 (2014) [C1]

Introduction: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondri... [more]

Introduction: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondrial DNA (mtDNA) under certain conditions, which is potently proinflammatory. We hypothesized that injury and orthopedic trauma surgery would induce NET production with mtDNA as a structural component. Methods: Neutrophils were isolated 8 trauma patients requiring orthopedic surgery postinjury and up to 5 days postoperatively. Four healthy volunteers provided positive and negative controls. Total hip replacement patients acted as an uninjured surgical control group. Neutrophil extracellular traps were visualized with DNA (Hoechst 33342TM/Sytox Green/MitoSox/MitoTracker) stains using live cell fluorescence microscopy with downstream quantitative polymerase chain reaction analysis of DNA composition. Results: Neutrophil extracellular traps were present after injury in all 8 trauma patients. They persisted for 5 days postoperatively. Delayed surgery resulted in NET resolution, but they reformed postoperatively. Total hip replacement patients developed NETs postoperatively, which resolved by day 5. Quantitative polymerase chain reaction analysis of NET-DNA composition revealed that NETs formed after injury and surgery were made of mtDNA with no detectable nuclear DNA component. Conclusions: Neutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications.

DOI 10.1016/j.jcrc.2014.07.013
Citations Scopus - 3
Co-authors Gough Au, Philip Hansbro, Zsolt Balogh
2014 Thomas J, Garg ML, Smith DW, 'Dietary resveratrol supplementation normalizes gene expression in the hippocampus of streptozotocin-induced diabetic C57Bl/6 mice', Journal of Nutritional Biochemistry, 25 313-318 (2014) [C1]

Diabetes is associated with cognitive impairment and brain aging, with alterations in hippocampal neurogenesis and synaptic plasticity implicated in these changes. As the prevalen... [more]

Diabetes is associated with cognitive impairment and brain aging, with alterations in hippocampal neurogenesis and synaptic plasticity implicated in these changes. As the prevalence of diabetes continues to rise, readily implemented strategies are increasingly needed in order to protect the brain's cognitive functions. One possibility is resveratrol (RES) (3,5,4- trihydroxystilbene), a polyphenol of the phytoalexin family that has been shown to be protective in a number of neuropathology paradigms. In the present study, we sought to determine whether dietary supplementation with RES has potential for the protection of cognitive functions in diabetes. Diabetes was induced using streptozotocin, and once stable, animals received AIN93G rodent diet supplemented with RES for 6 weeks. Genome-wide expression analysis was conducted on the hippocampus and genes of interest were confirmed by quantitative, real-time polymerase chain reaction. Genome-wide gene expression analysis of the hippocampus revealed that RES supplementation of the diabetic group resulted in 481differentially expressed genes compared to non-supplemented diabetic mice. Intriguingly, gene expression that was previously found significantly altered in the hippocampus of diabetic mice, and that is implicated in neurogenesis and synaptic plasticity (Hdac4, Hat1, Wnt7a, ApoE), was normalized following RES supplementation. In addition, pathway analysis revealed Jak-Stat signaling was the most significantly enriched pathway. The Jak-Stat pathway induces a pro-inflammatory signaling cascade, and we found most genes involved in this cascade (e.g. Il15, Il22, Socs2, Socs5) had significantly lower expression following RES supplementation. These data indicate RES could be neuroprotective and beneficial for the maintenance of cognitive function in diabetes. © 2014 Elsevier Inc.

DOI 10.1016/j.jnutbio.2013.11.005
Citations Scopus - 5Web of Science - 4
Co-authors Manohar Garg
2014 Parkinson GM, Dayas CV, Smith DW, 'Increased mitochondrial DNA deletions in substantia nigra dopamine neurons of the aged rat.', Current aging science, 7 155-160 (2014) [C2]
Co-authors Christopher Dayas
2014 James MH, Campbell EJ, Walker FR, Smith DW, Richardson HN, Hodgson DM, Dayas CV, 'Exercise reverses the effects of early life stress on orexin cell reactivity in male but not female rats', Frontiers in Behavioral Neuroscience, 8 (2014) [C1]
DOI 10.3389/fnbeh.2014.00244
Citations Scopus - 3Web of Science - 2
Co-authors Rohan Walker, Christopher Dayas, Deborah Hodgson
2014 McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, Balogh ZJ, 'Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery.', Journal of critical care, 29 1133.e1-1133.e5 (2014) [C1]
DOI 10.1016/j.jcrc.2014.07.013
Citations Scopus - 1
Co-authors Zsolt Balogh, Philip Hansbro, Gough Au
2013 Balogh ZJ, McIlroy DJ, Smith DW, Hansbro PM, 'The origin and the role of mitochondrial DNA in postinjury inflammation', Journal of Critical Care, 28 1099-1100 (2013) [C3]
DOI 10.1016/j.jcrc.2013.08.027
Citations Scopus - 2Web of Science - 2
Co-authors Philip Hansbro, Zsolt Balogh
2013 Thomas J, Garg ML, Smith DW, 'Altered expression of histone and synaptic plasticity associated genes in the hippocampus of streptozotocin-induced diabetic mice', Metabolic Brain Disease, 28 613-618 (2013) [C1]
DOI 10.1007/s11011-013-9418-y
Citations Scopus - 5Web of Science - 4
Co-authors Manohar Garg
2013 Thomas J, Garg ML, Smith DW, 'Dietary supplementation with resveratrol and/or docosahexaenoic acid alters hippocampal gene expression in adult C57Bl/6 mice', Journal of Nutritional Biochemistry, 24 1735-1740 (2013) [C1]

The hippocampus is an important brain structure for multiple cognitive functions, including memory formation. It is particularly sensitive to insults, such as stress, ischemia, an... [more]

The hippocampus is an important brain structure for multiple cognitive functions, including memory formation. It is particularly sensitive to insults, such as stress, ischemia, and aging; all of these can affect hippocampal and therefore cognitive function. To understand the potential of diet for the preservation of hippocampal function, we investigated the effects of dietary supplementation with resveratrol (RES) or docosahexaenoic acid (DHA), or their combination, on hippocampal gene expression in adult C57BL/6 mice. Animals in the supplemented group received either 50 mg/kg/day of RES or DHA, while the combination group received 50 mg/kg/day of each supplement. Dietary supplements were mixed with the AIN93G diet, and supplementation lasted 6 weeks. The control group received AIN93G diet alone for the same period. At the end of the experiment, the hippocampi were processed for genome-wide gene expression and pathway analyses. Most of the genes that were significantly altered were associated with inflammatory responses as determined by pathway analysis. RES-supplemented animals showed decreased expression of IL-6 ( P=001), MAPKapk2 ( P=015), and increased expression for PI3. KR2 ( P=034) and Wnt7a ( P=004) expression. DHA-supplemented animals showed a decreased IL-6 ( P=003) and an increased Wnt7a ( P=003) expression. Animals on the combination diet showed a decreased IL-6 ( P=005) and Apolipoprotien E ( ApoE) ( P=035) expression. Our findings demonstrate that hippocampal gene expression is significantly altered by all three dietary supplementation regimes. Moreover, our analysis indicates that RES and DHA likely exert their beneficial effects through antiinflammatory mechanisms. © 2013 Elsevier Inc.

DOI 10.1016/j.jnutbio.2013.03.002
Citations Scopus - 2Web of Science - 1
Co-authors Manohar Garg
2013 Cahif A, Parkinson GM, Dayas CV, Smith DW, 'Characterisation of mitochondrial DNA deletions by long-PCR in central nervous system regions of young, middle- and old-aged rats.', Current Aging Science, 6 232-238 (2013) [C1]
Citations Scopus - 1
Co-authors Christopher Dayas
2013 Brown AL, Day TA, Dayas CV, Smith DW, 'Purity and Enrichment of Laser-Microdissected Midbrain Dopamine Neurons', BIOMED RESEARCH INTERNATIONAL, (2013) [C1]
DOI 10.1155/2013/747938
Citations Scopus - 3
Co-authors Christopher Dayas
2012 Barreto RDA, Walker FR, Dunkley PR, Day TA, Smith DW, 'Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?', BMC Neuroscience, 13 1-12 (2012) [C1]
Citations Scopus - 7Web of Science - 9
Co-authors Rohan Walker, Peter Dunkley
2012 Dayas CV, Smith DW, Dunkley PR, 'An emerging role for the mammalian Target of Rapamycin (mTOR) in 'pathological' protein translation: Relevance to cocaine addiction', Frontiers in Pharmacology, 3 1-12 (2012) [C1]
Citations Scopus - 9Web of Science - 7
Co-authors Peter Dunkley, Christopher Dayas
2011 James MH, Charnley JL, Flynn JR, Smith DW, Dayas CV, 'Propensity to 'relapse' following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei', Neuroscience, 199 235-242 (2011) [C1]
Citations Scopus - 19Web of Science - 19
Co-authors Christopher Dayas
2011 James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV, 'Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking', International Journal of Neuropsychopharmacology, 14 684-690 (2011) [C1]
DOI 10.1017/s1461145711000423
Citations Scopus - 45Web of Science - 42
Co-authors Christopher Dayas
2011 Brown AL, Flynn JR, Smith DW, Dayas CV, 'Down-regulated striatal gene expression for synaptic plasticity-associated proteins in addiction and relapse vulnerable animals', International Journal of Neuropsychopharmacology, 14 1099-1110 (2011) [C1]
Citations Scopus - 11Web of Science - 9
Co-authors Christopher Dayas
2010 James MH, Charnley JL, Jones E, Levi E, Yeoh JW, Flynn JR, et al., 'Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour', Plos One, 5 e12980 (2010) [C1]
DOI 10.1371/journal.pone.0012980
Citations Scopus - 25Web of Science - 22
Co-authors Christopher Dayas
2009 McInerny SC, Brown AL, Smith DW, 'Region-specific changes in mitochondrial D-loop in aged rat CNS', Mechanisms of Ageing and Development, 130 343-349 (2009) [C1]
DOI 10.1016/j.mad.2009.01.008
Citations Scopus - 13Web of Science - 10
2009 Brown AL, Smith DW, 'Improved RNA preservation for immunolabeling and laser microdissection', RNA: A Publication of the RNA Society, 15 2364-2374 (2009) [C1]
DOI 10.1261/rna.1733509
Citations Scopus - 13Web of Science - 10
2007 Smith DW, Jinnah HA, 'Role of neuronal nitric oxide in the dopamine deficit of HPRT-deficient mice', Metabolic Brain Disease, 22 39-43 (2007) [C1]
DOI 10.1007/s11011-007-9044-7
Citations Scopus - 3Web of Science - 3
2004 Smith DW, Friedmann T, 'Discrepant effects of culture conditions on survival and function of dopaminergic neurons.', Neuroreport, 15 1025-1028 (2004) [C1]
DOI 10.1097/00001756-200404290-00018
2003 Tokumine J, Kakinohana O, Cizkova D, Smith DW, Marsala M, 'Changes in spinal GDNF, BDNF and NT-3 expression after transient spinal cord ischemia in the rat.', Neuroscience Research, 74 552-561 (2003) [C1]
DOI 10.1002/jnr.10760
2003 Smith DW, Day TA, 'Catecholamine and oxytocin cells respond to hypovolaemia as well as hypotension', Neuroreport, 14 1493-1495 (2003) [C1]
DOI 10.1097/00001756-200308060-00018
2002 Visser JE, Smith DW, Fried T, Rothstein JD, Jinnah HA, 'Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.', Brain Res Dev Brain Res, (2002) [C1]
2000 Smith D, 'Characterization of the Dopamine Defect in Primary Cultures of Dopaminergic Neurons from Hypoxanthine Phosphoribosyltransferase Knockout Mice', Molecular Therapy, 1 486-491 (2000)
DOI 10.1006/mthe.2000.0057
1999 Buller KM, Smith DW, Day TA, 'Differential recruitment of hypothalamic neuroendocrine and ventrolateral medulla catecholamine cells by non-hypotensive and hypotensive hemorrhages', BRAIN RESEARCH, 834 42-54 (1999)
DOI 10.1016/S0006-8993(99)01539-5
Citations Web of Science - 59
1999 Buller KM, Smith DW, Day TA, 'NTS catecholamine cell recruitment by hemorrhage and hypoxia', NEUROREPORT, 10 3853-3856 (1999)
DOI 10.1097/00001756-199912160-00024
Citations Web of Science - 26
1995 SMITH DW, SIBBALD J, KHANNA S, DAY TA, 'RAT VASOPRESSIN CELL RESPONSES TO SIMULATED HEMORRHAGE - STIMULUS-DEPENDENT ROLE FOR A1 NORADRENERGIC NEURONS', AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 268 R1336-R1342 (1995)
Citations Web of Science - 41
1995 SMITH DW, DAY TA, 'HYPOVOLEMIC AND OSMOTIC STIMULI INDUCE DISTINCT PATTERNS OF C-FOS EXPRESSION IN THE RAT SUBFORNICAL ORGAN', BRAIN RESEARCH, 698 232-236 (1995)
DOI 10.1016/0006-8993(95)00975-V
Citations Web of Science - 22
1995 Smith DW, Buller KM, Day TA, 'Role of ventrolateral medulla catecholamine cells in hypothalamic neuroendocrine cell responses to systemic hypoxia', JOURNAL OF NEUROSCIENCE, 15 7979-7988 (1995)
Citations Web of Science - 72
1994 SMITH DW, DAY TA, 'C-FOS EXPRESSION IN HYPOTHALAMIC NEUROSECRETORY AND BRAIN-STEM CATECHOLAMINE CELLS FOLLOWING NOXIOUS SOMATIC STIMULI', NEUROSCIENCE, 58 765-775 (1994)
DOI 10.1016/0306-4522(94)90453-7
Citations Web of Science - 49
1994 KHANNA S, SIBBALD J, SMITH DW, DAY TA, 'INITIATION OF RAT VASOPRESSIN CELL RESPONSES TO SIMULATED HYPOTENSIVE HEMORRHAGE', AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 267 R1142-R1149 (1994)
Citations Web of Science - 20
1993 SMITH DW, DAY TA, 'NEUROCHEMICAL IDENTIFICATION OF FOS-POSITIVE NEURONS USING 2-COLOR IMMUNOPEROXIDASE STAINING', JOURNAL OF NEUROSCIENCE METHODS, 47 73-83 (1993)
DOI 10.1016/0165-0270(93)90023-K
Citations Web of Science - 41
1992 DAY TA, SIBBALD J, SMITH DW, 'A1-NEURONS AND EXCITATORY AMINO-ACID RECEPTORS IN RAT CAUDAL MEDULLA MEDIATE VAGAL EXCITATION OF SUPRAOPTIC VASOPRESSIN CELLS', BRAIN RESEARCH, 594 244-252 (1992)
DOI 10.1016/0006-8993(92)91131-W
Citations Web of Science - 45
Show 34 more journal articles

Conference (13 outputs)

Year Citation Altmetrics Link
2015 McIlroy DJ, Bigland M, White AE, Hardy BM, Lott N, Smith DW, Balogh ZJ, 'Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery', Journal of Trauma and Acute Care Surgery (2015)

Background: Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on ... [more]

Background: Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on mtDNA concentration is unknown. We hypothesized that mtDNA and nuclear DNA (nDNA) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly. Methods: In this prospective pilot, plasma was sampled from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points. Healthy control subjects (n = 20)were sampled.DNAwas extracted, and the mtDNA and nDNAwere assessed using quantitative polymerase chain reaction. Markers of cell necrosis were also assayed (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase). Results: The free plasma mtDNA and nDNA levels (ng/mL) were increased in trauma patients compared with healthy controls at all time points (mtDNA: preoperative period, 108 [46-284]; postoperative period, 96 [29-200]; 7 hours postoperatively, 88 [43-178]; 24 hours, 79 [36-172]; 3 days, 136 [65-263]; 5 days, 166 [101-434] [healthy controls, 11 (5-19)]) (nDNA: preoperative period, 52 [25-130]; postoperative period, 100 [35-208]; 7 hours postoperatively, 75 [36-139]; 24 hours postoperatively, 85 [47-133]; 3 days, 79 [48-117]; 5 days, 99 [41-154] [healthy controls, 29 (16-54)]). Elevated DNA levels did not correlate with markers of cellular necrosis. mtDNA was significantly elevated compared with nDNA at preoperative period (p = 0.003), 3 days (p = 0.003), and 5 days (p = 0.0014). Preoperative mtDNA levelswere greater with shorter time from injury to surgery (p = 0.0085). Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion (p = 0.0017). Major pelvic surgery (vs. minor) was associated with greater mtDNA release 5 days postoperatively (p G 0.05). Conclusion: This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery. Postoperative, circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration. Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation. Level of Evidence: Prospective study, level III.

DOI 10.1097/TA.0000000000000519
Citations Scopus - 2
Co-authors Zsolt Balogh
2014 Khan SI, Hübner PP, Smith DW, Brichta AM, Migliaccio AA, 'Ageing reduces vestibulo-ocular reflex adaptation in mice J Vestib Res', Journal of Vestibular Research: Equilibrium and Orientation: an international journal of experimental and clinical vestibular science (2014) [E3]
DOI 10.3233/VES-140517
Co-authors Alan Brichta
2013 Bigland M, Parkinson G, Brichta AM, Smith DW, 'Evidence for mitochondrial DNA deletions in vestibular hair cells of the aged rat', Proceedings of the Australian Neuroscience Society, Melbourne (2013) [E3]
Co-authors Alan Brichta
2012 Parkinson GM, Smith DW, 'Age-related increase in mitochondrial DNA copy number in midbrain dopamine neurons of the rat', Abstracts. Australian Neuroscience Society 32nd Annual Meeting, Gold Coast, Queensland (2012) [E3]
2012 James MH, Charnley JL, Levi EM, Dunkley PR, Smith DW, Dickson PW, Dayas CV, 'A role for the mTOR pathway in the development of addiction', Abstracts. Australian Neuroscience Society 32nd Annual Meeting, Gold Coast, Queensland (2012) [E3]
Co-authors Phil Dickson, Christopher Dayas, Peter Dunkley
2012 Thomas J, Smith DW, Garg ML, 'Early molecular signature of neuro-protection in hippocampus of resveratrol diet fed C57BL/6 mice', Resveratrol 2012. 2nd International Conference of Resveratrol and Health, Leicester, UK (2012) [E3]
Co-authors Manohar Garg
2012 Brown AL, Flynn JR, Dayas CV, Smith DW, 'Altered gene expression in cell signalling pathways of midbrain dopamine neurons from addiction and relapse vulnerable animals', Drug and Alcohol Review: Abstracts of the Australasian Professional Society on Alcohol and other Drugs Conference 2012, Melbourne, Vic (2012) [E3]
Co-authors Christopher Dayas
2012 Dayas CV, Quinn RK, Goldie BJ, Brown AM, Levi EM, Smith DW, Cairns MJ, 'Association of miRNAs with addiction-relevant synaptic plasticity genes', Abstract Book. Biological Psychiatry Australia Scientific Meeting, Parkville, Vic (2012) [E3]
Co-authors Murray Cairns, Christopher Dayas
2011 Thomas J, Smith DW, Garg ML, 'Dietary supplementation with resveratrol normalizes histone deacetylase (HDAC4) in the hippocampus of streptozotocin-induced diabetic mice', Australasian Medical Journal, Queenstown, NZ (2011) [E3]
Co-authors Manohar Garg
2011 Barreto RDA, Walker FR, Dunkley PR, Day TA, Smith DW, 'Alteration of neurotrophic factor pathway gene expression in the rat infralimbic medial prefrontal cortex by subchronic restraint stress is reversed by fluoxetine', Posters. Australian Neuroscience Society 31st Annual Meeting, Auckland, New Zealand (2011) [E3]
Co-authors Rohan Walker, Peter Dunkley
2010 Thomas J, Smith DW, Garg ML, 'Dietary supplementation with resveratrol reduces erythrocyte arachidonic and docosahexaenoic acids levels in diabetic mice', Proceedings of the Nutrition Society of Australia, Perth, WA (2010) [E3]
Co-authors Manohar Garg
2007 McInerny SC, Brown AL, Smith DW, 'Brain region-specific decrease in mitochondrial D-loop in aged rats (Poster)', 7th IBRO 2007 World Congress of Neuroscience Program, Melbourne (2007) [E3]
1995 Day TA, Smith DW, Buller KM, 'Regulation of neurosecretory cell activity by A1 noradrenergic neurons', 1st Joint World Congress of Neurohypophysis and Vasopressin, Nasu Japan (1995)
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Grants and Funding

Summary

Number of grants 15
Total funding $4,719,925

Click on a grant title below to expand the full details for that specific grant.


20151 grants / $25,000

Maintaining our cognitive abilities as we grow old: preventing the effects of ageing on the brain$25,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Doug Smith, Doctor Frederick Walker
Scheme Project Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1500078
Type Of Funding External
Category EXTE
UON Y

20131 grants / $35,000

20122 grants / $313,375

The effects of ageing on the peripheral vestibular system. Can ageing-related functional decline be reduced or prevented?$298,375

Funding body: Garnett Passe and Rodney Williams Memorial Foundation

Funding body Garnett Passe and Rodney Williams Memorial Foundation
Project Team Doctor Doug Smith
Scheme Project Grant
Role Lead
Funding Start 2012
Funding Finish 2012
GNo G1100935
Type Of Funding Aust Competitive - Non Commonwealth
Category 1NS
UON Y

2011 Emerging Research Leaders Program$15,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Doug Smith
Scheme Emerging Research Leaders Program
Role Lead
Funding Start 2012
Funding Finish 2012
GNo G1200307
Type Of Funding Internal
Category INTE
UON Y

20111 grants / $25,000

Brain Mechanisms Conferring Psychostimulant Addiction$25,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Chris Dayas, Emeritus Professor Peter Dunkley, Doctor Doug Smith
Scheme Near Miss Grant
Role Investigator
Funding Start 2011
Funding Finish 2011
GNo G1001052
Type Of Funding Internal
Category INTE
UON Y

20103 grants / $599,000

Laser microdissection microscopy system for cell and development biology$350,000

Funding body: ARC (Australian Research Council)

Funding body ARC (Australian Research Council)
Project Team Professor Eileen McLaughlin, Conjoint Professor Keith Jones, Laureate Professor John Aitken, Associate Professor Brett Nixon, Doctor Shaun Roman, Professor Alan Brichta, Doctor Rick Thorne, Doctor Doug Smith, Associate Professor David McCurdy, Conjoint Professor Ray Rose, Professor Christopher Grof, Emeritus Professor Leonie Ashman, Professor Gordon Burns, Doctor Brett Graham, Associate Professor Paul Tooney, Professor Roger Smith, Laureate Professor Paul Foster, Professor Trevor Day, Professor Robert Callister
Scheme Linkage Infrastructure Equipment & Facilities (LIEF)
Role Investigator
Funding Start 2010
Funding Finish 2010
GNo G0190369
Type Of Funding Scheme excluded from IGS
Category EXCL
UON Y

ABI 7500 Real Time PCR System $34,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Rick Thorne, Doctor Nikki Verrills, Conjoint Associate Professor Murray Cairns, Associate Professor Paul Tooney, Doctor Doug Smith, Professor Gordon Burns, Emeritus Professor Leonie Ashman, Conjoint Professor Keith Jones, Doctor Charles De Bock, Doctor Chris Dayas, Doctor Brett Graham, Doctor Martin Horan, Doctor Rebecca Lim, Doctor Severine Roselli, Doctor Larisa Bobrovskaya, Doctor Kathryn Skelding, Doctor Frederick Walker, Doctor Jude Weidenhofer, Associate Professor Philip Bolton, Professor Alan Brichta, Professor Robert Callister, Professor Trevor Day, Associate Professor Phillip Dickson, Professor Manohar Garg, Doctor Phil Jobling, Associate Professor Derek Laver, Associate Professor Eugene Nalivaiko, Emeritus Professor John Rostas
Scheme Equipment Grant
Role Investigator
Funding Start 2010
Funding Finish 2010
GNo G1000055
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20081 grants / $538,500

Dopamine mechanisms conferring resilience to depression: A new antidepressant target$538,500

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Trevor Day, Emeritus Professor Peter Dunkley, Professor David Pow, Doctor Doug Smith
Scheme Project Grant
Role Investigator
Funding Start 2008
Funding Finish 2008
GNo G0187604
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

20072 grants / $40,000

Vulnerability to depression: the role of dopamine pathways$20,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Professor Trevor Day, Emeritus Professor Peter Dunkley, Doctor Doug Smith, Professor David Pow
Scheme Near Miss Grant
Role Investigator
Funding Start 2007
Funding Finish 2007
GNo G0187196
Type Of Funding Internal
Category INTE
UON Y

Characterisation of the brain mechanisms linking vulnerability to stress and vulnerability to drug addiction$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Professor Trevor Day, Doctor Chris Dayas, Doctor Doug Smith
Scheme Project Grant
Role Investigator
Funding Start 2007
Funding Finish 2007
GNo G0187255
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

20042 grants / $13,679

Characterisation of age-related gene expression changes in midbrain dopamine neurons$12,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Doug Smith
Scheme New Staff Grant
Role Lead
Funding Start 2004
Funding Finish 2004
GNo G0184998
Type Of Funding Internal
Category INTE
UON Y

Society for Neuroscience Annual Meeting, 23-27 October 2004$1,679

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Doug Smith
Scheme Travel Grant
Role Lead
Funding Start 2004
Funding Finish 2004
GNo G0184814
Type Of Funding Internal
Category INTE
UON Y

20031 grants / $2,489,371

Genetic aberrations in HPRT deficiency$2,489,371

Funding body: National Institute of Neurological Disorders (NIH)

Funding body National Institute of Neurological Disorders (NIH)
Project Team
Scheme Project
Role Investigator
Funding Start 2003
Funding Finish 2007
GNo
Type Of Funding External
Category EXTE
UON Y

20011 grants / $641,000

Array screening for Lesch-Nyhan disese$641,000

Funding body: NICH (NIH)

Funding body NICH (NIH)
Project Team
Scheme R21
Role Investigator
Funding Start 2001
Funding Finish 2003
GNo
Type Of Funding External
Category EXTE
UON Y
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Research Supervision

Number of supervisions

Completed6
Current4

Total current UON EFTSL

PhD1.75

Current Supervision

Commenced Level of Study Research Title / Program / Supervisor Type
2012 PhD Ageing of the Inner Ear Balance System
Human Biology, Faculty of Health and Medicine, The University of Newcastle
Principal Supervisor
2012 PhD The Role of Mitochondrial DNA in the Post-Injury "Inflammatory" Response Following Major Trauma
General Medicine, Faculty of Health and Medicine, The University of Newcastle
Co-Supervisor
2011 PhD Ageing of the Somatic Motor Nervous System: A Mitochondrial and Nuclear Genome Perspective
Medical Science, Faculty of Health and Medicine, The University of Newcastle
Principal Supervisor
2007 PhD Role of dopamine in depression
Medical Science, University of Newcastle
Principal Supervisor

Past Supervision

Year Level of Study Research Title / Program / Supervisor Type
2015 Masters Nucleotide Excision Repair of UVA-Induced DNA Damage: Regulation in Sunlight-Induced Melanoma
Health, Faculty of Health and Medicine, The University of Newcastle
Co-Supervisor
2014 PhD The Role of Cocaine- and Amphetamine-Regulated Transcript (CART) and Orexin in Drug-Seeking and Addiction-Related Behaviours
Human Biology, Faculty of Health and Medicine, The University of Newcastle
Co-Supervisor
2013 PhD Effects of Anti-Inflammatory Bioactives on Diabetes-Induced Changes in Cognition-Related Gene Expression in the Hippocampus
Medical Science, Faculty of Health and Medicine, The University of Newcastle
Co-Supervisor
2012 PhD Molecular Correlates of Dopamine Signalling in Addiction Vulnerability
Human Biology, Faculty of Health and Medicine, The University of Newcastle
Principal Supervisor
2012 PhD Dopaminergic Pathway Imbalance in the Neurobiology of Depression
Human Biology, Faculty of Health and Medicine, The University of Newcastle
Principal Supervisor
2006 Honours Role of mitochondrial D-loop in aging brain
Medical Science, University of Newcastle
Principal Supervisor
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Dr Doug Smith

Position

Senior Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Anatomy

Contact Details

Email douglas.smith@newcastle.edu.au
Phone (02) 4921 7108
Fax (02) 4921 8667

Office

Room MS306B
Building Medical Sciences
Location Callaghan
University Drive
Callaghan, NSW 2308
Australia
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