The University of Newcastle, Australia

The Importance of Classical Versus Backdoor Androgen Production Pathways in Masculinisation, Fertility, and Lifelong Male Health

Closing Date: 31 July 2020


PhD Scholarship

Male health and wellbeing are supported by androgens. Reduction in androgen levels associated with metabolic disorders, and many age-related degenerative conditions. Understanding how androgens are produced and how they act is essential if we are to promote lifelong male health

Egg Fertilisation

Male development, fertility, and lifelong health are all androgen-dependent. Perturbed androgen action at any stage of life significantly impacts the quality of life ([1]), and low androgens are an independent risk factor for all-cause early death ([2]). Thus, understanding the fundamental regulation of androgen production and action is essential if we are to support healthy aging throughout life. Androgens are synthesized by Leydig cells within the interstitial compartment.

Testosterone can act:

  • Directly within the testis and local environment, and or
  • Indirectly, once secreted in the bloodstream, via the conversion into dihydrotestosterone (DHT).

This route, the classical pathway, initiates masculinization and later promotes male fertility and health. Recently, an alternative metabolic route to DHT conversion, the backdoor pathway, was identified bypassing the testosterone step [3-8] and reviewed in [9, 10]. In humans, loss of function (LOF) mutations in HSD17B3 [11], SRD5A2 [12] all result in perturbed sexual differentiation, thus the pathway defined by HSD17B3 > T > SRD5A2 > DHT has constituted the ‘classical’ paradigm for androgen signaling in male development, fertility, and lifelong male health for decades. One of the more curious observations arising from HSD17B3 or SRD5A2 LOF individuals is that they undergo late-onset virilisation during puberty, suggesting that the classical pathway does not encapsulate the entirety of the androgen story.

Together these observations demonstrate the importance of both the classical and backdoor pathways in supporting male development and later male function, across the mammalian kingdom. However, how these pathways intersect both inside and outside of the testis, and the relative importance of each pathway for specific androgen-responsive endpoints during sexual development and throughout later life has been impossible to dissect, as animal models have simply not been available. To support the objectives of this project we have generated a double KO for Hsd17b3 and Srd5a1, to selectively block the classical, backdoor or both androgen production pathways simultaneously.

This project will utilise this unique mouse colony alongside in silico modeling, in vivo reporter analysis, and direct gene knockdown in live human testis tissue to establish the fundamental roles classical and backdoor androgen production play in masculinisation, puberty, male reproductive function, and lifelong male health. Completion of this project will transform our fundamental understanding of male endocrinology, with implications for future clinical, veterinary and agricultural practices. And will provide significant new insight into the control of androgen production in the male, which will underpin future efforts to support lifelong health and wellbeing in both humans and animals.

Hypothesis:

The classical and backdoor androgen pathways form an integrated and reciprocally responsive system essential for male development, adult function, and lifelong male health.

Project Summary overview:

Using a combination of in vivo, ex vivo, in vitro studies and in silico modelling, such as transgenic mouse models, “gene therapy”, applied biotechnologies as well as usual bio-molecular techniques, this project will define the fundamental control of androgen signaling through the classical and backdoor pathways.

Common approaches:

  • Generate a dynamic in silico model of androgen production under different conditions
  • Determine the roles of classical and backdoor androgen pathways during testis development and masculinisation
  • Define the roles for classical and backdoor androgen pathways in postnatal maturation and adult function
  • Enhance classical pathway activity as a novel therapeutic tool
  • Determine the impact of the loss of HSD17B3 in Females

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: Dr Diane Rebourcet

Available to: Domestic students

PhD

Eligibility Criteria

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 honors degree in a Biomedical Science or equivalent degree with laboratory experience.

Supervisors:

Dr Diane Rebourcet

Professor Lee Smith

Application Procedure

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
Email L.B.Smith@newcastle.edu.au

PhD and Research MastersFind out more