NHMRC Research Fellowship (PRF): Endocrine control of metabolic disease (2014–2018)
Abstract:
I am a leading endocrinology researcher with >20 yrs experience and an international reputation (h-index 41) in Nuclear Hormone Receptor (NR) action. I study NR (and coregulator)-dependent endocrine regulation of the 21st century
epidemics of obesity, type2 diabetes, and cancer. The NR family are ligand-dependent DNA-binding proteins that translate nutritional, hormonal and pathophysiological signals into gene regulation. Proteins have been identified that belong to the NR family, but the molecules that regulate their activity are unknown and are denoted as orphans. The orphans provide a platform for the unearthing of new therapeutic
targets/pathways/compounds that may have utility in metabolic disease and cancer, underscored by the efficacy of NR medicinals that account for the top 15% of pharmaceuticals. My VISION and research program are directed toward elucidating the organ specific roles of orphan NRs (and coregulators) in obesity, type2 diabetes and breast cancer. Significantly, we wish to therapeutically exploit these pharmacologic targets in the context of metabolic disease and cancer. To facilitate the translation of our NR & metabolic expertise in transgenic models, I have fostered multidisciplinary teams to address these objectives, including an Obesity Research Centre (GM-Director) and a national consortium to study breast cancer. In 2012-13 we
examined human breast cancer cohorts and identified NR targets for therapeutic exploitation/prognosis-(P001322687) & epigenetic coregulators markers for metastasis free survival(P001322540). We have initiated partnerships to identify novel drugs for these NR targets, that also have utility in metabolic disease. This builds on expertise in NRs/metabolism, e.g. P00098501, we re-examined halofenate (a ¡¥70s lipid lowering compound), and demonstrated it was an anti-diabetic PPARg ¿nmodulator. Metabolex Inc exploited halofenate and reached phase 2/3 clinical trials as anti-diabetic, and is in phase 2 for Gout.
