Completed Genetics & Molecular Biology Diabetes, Hormones & Metabolism

Novel mechanisms in adrenal and reproductive biology.

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £1.4M
Period Aug 2012 — Jan 2018

In plain English

AI plain-English summary

A single gene-regulating protein, SRY, flips the switch that turns a generic embryonic gonad into a testis, and this project will map the full chain of molecular commands that follows. The work addresses a fundamental gap: we know the master switches for sex development and steroid hormone production, but not the many downstream genes they control. When those downstream genes break, the result can be disorders of sex development, adrenal failure, or infertility. The researchers will build mathematical models of gene expression data to predict which unknown factors are critical, then test those predictions in human cells. They will also sequence the genomes of patients with unexplained adrenal or reproductive disorders to find rare, disease-causing variants. If successful, the project will turn a list of suspected genes into a validated network of targets for diagnosis. Clinicians could then pinpoint the molecular cause of a child’s ambiguous genitalia or a woman’s premature ovarian failure, rather than relying on descriptive labels. The work is fundamentally curiosity-driven—it asks how a handful of proteins orchestrate the development of entirely different organs—but the same approach has previously uncovered the genetic basis of conditions such as congenital adrenal hyperplasia, transforming newborn screening and treatment.

View original technical description
This proposal addresses five key research questions in human adrenal and reproductive biology. These aims are supported by data we have acquired over the past five years, so can be addressed in a timely manner. Aim 1 uses mathematical modelling of gene expression data to identify and characterise novel targets of SRY/SOX9 in human testis development. These factors could be disrupted in disorders of sex development (DSD). Aim 2 develops the modelling approach to identify novel components of stero idogenesis in the adrenal gland and testis. These factors would be implicated in disorders of adrenal, gonadal or placental steroid synthesis. Aim 3 characterises ovarian germ cell development and pluripotency. Disruption of germ cell development would impair ovarian reserve and infertility. Aim 4 investigates new disorders of human adrenal and reproductive function using high throughput sequencing approaches. The biological significance of rare variants will be interpreted in relation to our ex pression datasets. Aim 5 expands our understanding of steroidogenic factor-1 (SF-1, NR5A1) and human disease through knowledge curation, engagement, and models of the long-term metabolic and reproductive effects of SF-1 dysfunction. Taken together, this interrelated body of work addresses fundamental biological questions and has strong translational impact on human disease and fertility.

View the original record at the funder ↗

Researchers

John Achermann (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Investigation into the role of HOX factors in gonad and adrenal steroidogenesis
Somatic adaptation and sex differences in human endocrine development and disease
Epigenetic mechanisms of androgen regulated gene expression
Interrogating the role of SGPL1 in adrenal/gonadal development and acute steroidogenesis
A genomics approach to unravelling the link between steroid hormone dysregulation and cardio-metabolic disease

Original classification

Senior Research Fellowship Clinical Renewal

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