Developing Alternative Treatments For Male Reproductive And Endocrine Disorders Using Deliverable Transgenics As Gene Therapy
Closing Date: 31 July 2020
This project focuses on the development of non-viral vectors for the delivery of transgenics to the adult testis. Findings from the proposed project will be applicable to both animal and human research for the investigation of male reproductive disorders.
Background Androgens are crucial for male health and wellbeing. Over 20% of men over 40 experience hypogonadism (low circulating testosterone levels) (Tajar, Forti et al. 2010) resulting in impaired reproductive physiology, an increased risk of cardiovascular-metabolic diseases and earlier mortality (Laughlin, Barrett-Connor et al. 2008, Saad and Gooren 2009, Saad and Gooren 2010, Morris and Channer 2012, Pye, Huhtaniemi et al. 2014). The causes of hypogonadism are multifactorial with both genetics and aging dramatically impacting Leydig cell function and number. Currently, treatment is limited to hormone replacement therapy; requiring expensive long term recurrent intervention and often inducing side effects with associated risks yet to be fully defined (Gagliano-Juca and Basaria 2019).
Therefore, the identification of new strategies for regulating endogenous steroidogenesis that are:
- Under hypothalamic-pituitary-gonadal axis control
- Address the multifactorial nature of hypogonadism, is crucial for maintaining male health throughout life.
Accelerating advancements in gene delivery technologies promise novel, personalised therapeutics that would prove beneficial for the millions of hypogonadal and infertile men. In 2016, >67% of gene therapy clinical trials utilised viral vectors as a delivery mechanism, technology the Smith group has recently refined for targeting Sertoli and Leydig cells, the somatic cells essential for steroidogenesis. Utilising this technology, we have rescued testis function in mouse models of disrupted steroidogenesis and infertility. This demonstrates the potential of this technology to treat male reproductive disorders such as hypogonadism and infertility. Though an ideal approach for treating hypogonadism, viral vectors are expensive to produce, have a questionable safety profile and can be difficult to manipulate . Drawing from the group’s expertise in deliverable transgenics in the testis , the student will first develop and characterise targeted organic nanoparticles as an alternative delivery system in the adult mouse testis before utilising this technology in proof of principle experiments, demonstrating rescue of testis function in mouse models of male reproductive disorders.
Project Summary Overview:
- Design and validate testicular somatic cell-targeting peptides.
- Generate and confirm targeting specificity of nanoparticles and fluorescent transgene delivery in vitro.
- Confirm cell-specific targeting of nanoparticles and delivery of fluorescent transgene in vivo.
- Utilise technology in proof of principle gene rescue experiments, demonstrating rescue of testis function following the delivery of ‘gene therapy nanoparticles’ in vivo.
Health/Wealth Benefits Tackling a complex and multifactorial condition such as hypogonadism is expected to have a significant impact on chronic and age-related clinical conditions associated with this disorder including cardiovascular disease, diabetes, obesity, and metabolic syndrome.
This project focuses on the development of non-viral vectors for the delivery of transgenics to the adult testis. Findings from the proposed project will be applicable to both animal and human research for the investigation of male reproductive disorders; nanoparticle targeting peptides can be designed and tested in vitro to confirm targeting in both murine and human testicular cells. The development of this technology will provide potential alternative treatments to those currently available to those suffering from male reproductive and endocrine disorders.
In addition to this, the development of this technology will also have wider implications within the research for the in vitro and in vivo modeling of human endocrine disorders.
Approaches and Skills:
- Development and investigation of transgenic mouse models * Analysis of testicular phenotypes
- Use of nanoparticle vector technologies
- Biochemistry techniques (Immunohistochemistry, western blotting)
- Cell Culture (2D and potentially 3D cell culture, viral and non-viral transfections)
- Molecular Biology (RNA/DNA/Protein extraction, PCR, qRT-PCR, Primer design, and validation)
- Cloning & vector construction
PhD Scholarship details
Funding: $28,092 per annum (2020 rate) indexed annually. The living allowance scholarship is for 3.5 years and the tuition fee scholarship is for four years.
Supervisor: Professor Lee Smith
Available to: Domestic students
The candidate will join a growing multi-disciplinary team, consisting of experts in the field. Applicants should have a strong work ethic, self-motivation, developed communication and teamwork skills. We are seeking applications from individuals who have completed first class or second-class upper honours degree in a Biomedical Science or equivalent degree with laboratory experience.
Professor Lee Smith
Dr Annalucia Darbey
Interested applicants should send an email expressing their interest along with scanned copies of their academic transcripts, CV, a brief statement of their research interests and a proposal that specifically links them to the research project.
Please send the email expressing interest to L.B.Smith@newcastle.edu.au by 5pm on 31 July 2020.
Applications Close 31 July 2020
|Contact||Professor Lee Smith|
|Phone||(02) 4921 5906|
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