Grant: Project Grant

Infertility affects 12-15 % of couples of reproductive age in developed countries, and some 186 million people worldwide. The lack of understanding of the mechanisms of infertility represents a major gap in our knowledge of reproductive biology. Two major issues have been identified, the first being activation of the ovarian reserve of primordial follicles. The second is ovarian aging, where there is precocious depletion of the primordial follicle population and inflammation and fibrosis of the ovary. We are exploring how nuclear receptors, regulate cell functions in the ovary and in other tissues. These molecules (e.g. the estrogen receptor) have widespread roles in reproduction. There is a class of these receptors where the signals that activate the receptor are unknown. These are the orphan nuclear receptors. We propose to continue to study the mechanism of of one of these orphan receptors, known as SF-1, that we have shown to be essential for formation and maintenance of the ovarian reserve. The focus will be on the mechanisms of SF-1 activation of the primordial follicles and its role in preventing ovarian aging and depletion of the ovarian reserve. Our study will employ transgenic mouse models where these receptors have been depleted, and donated human ovarian samples in biobanks. Global approaches will reveal the mechanisms of orphan nuclear receptors in infertility, and may lead to the discovery of therapeutic means to address human infertility.