Female infertility: deciphering the mechanisms that perturb ERa-signalling in the hypothalamus. (360G-Wellcome-105545_Z_14_Z)

There is an increasing clinical demand for affordable and effective treatments for female infertility associated with obesity and diabetes. However, despite its importance to the health of the population, the mechanistic details of how metabolic pathways affect the female reproductive axis are poorly understood. There are evidence in mice, including my own data, that infertility associated with nutrient deficit is caused by the failure of hypothalamic ER-alpha to appropriately respond to estroge n-stimulation. Decreased leptin signaling has been implicated in this process. However, the molecular details of how this occurs are not known. Therefore, the aim of the proposal is to determine what governs ER-alpha activity during health and disease. I have preliminary data that suggest co-activator and co-repressor interactions play an important role. I will identify co-factors that differentially modulate the activity of ligand-bound ER-alpha in two distinct regions of the hypothalamus to maintain fertility during favorable conditions. The mechanism of action of these co-factors will be determined using in-vitro assays and tissue-specific KO mice. Then, I will assess the importance of these co-factors in regulating female reproduction in models of metabolic-stress, including leptin-treatment. Understanding the dynamics of the functional ER-interactome will inform novel strategies for assisted reproduction therapy.