NHMRC Research Fellowship (SPRF): Disorders of gonadal development: Molecular approaches to improved patient care (2014–2018)
Abstract:
Disorders of sex development (DSDs, including intersex, XY femaleness and XX maleness) are in many cases caused by failure of the testicular or ovarian development pathways, but many DSDs remain unexplained at the molecular level. Current management strategies rely largely on examination and hormonal analysis of the patient, rather than knowledge of the underlying genetic lesion.
Type II testicular germ cell tumours (TGCT) represent the most common malignancy in men under 30. Although dysregulation of fetal germ cell control mechanisms is implicated in TGCT formation, the molecular cause has remained unknown.
The VISION underpinning this Fellowship is to identify the causes of DSD resulting from gonadal dysgenesis, using new genomic analysis technologies and tools. Further, recent discoveries in my laboratory have provided a basis for early, cheap and non-invasive detection of type II TGCT, and for developing targeted molecular therapies for this disease.
AIMS of this work are:
1. DSD: To sequence the transcriptome of the developing gonads in the mouse at key developmental stages, to place the resultant genes and noncoding elements into networks using sophisticated bioinformatic tools, and to prioritize the resultant transcripts for mutation searching in a bank of human DSD patient DNA samples; and 2. Testis cancer: To evaluate the Nodal co-receptor Cripto as a tractable cell surface marker for human type II TGCT, to develop the first mouse model for this disorder as a tool for studying the biology of TGCT and as a pre-clinical therapeutic model, and to evaluate the ability of blockers
of Cripto function (antibodies, small molecules) as anti-cancer therapeutics.
OUTCOMES will include a comprehensive suite of molecular diagnostics for DSD, accurate diagnosis and prognosis for evidence-based clinical management of DSD children, and rapid, cost-effective, non-invasive strategies to diagnose and treat testicular cancer
