Interrogating the Role of HSF1 in Ovarian Stress

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT It has long been known that physiological stress during gestation can lead to the alteration of stress and metabolic responses over multiple generations. Such information must be transmitted through the germline; however, the mechanistic effects of physiological stress on the germline and, more broadly, whether stress- related changes occur at the level of the germ cells themselves remain unexplored. The maternal hypothalamic- pituitary-adrenal axis is activated upon gestational stress and its downstream effectors are glucocorticoids, a class of steroid hormones, which are released into the bloodstream then bind to the ubiquitously expressed Glucocorticoid Receptor (GR). While stress-induced levels of glucocorticoids are known to impair oocyte competence in adult women, their impact on the fetal oocyte remains largely unexplored. Interestingly, GR has been shown to downregulate the activity of Heat Shock Factor 1 (HSF1). While HSF1 is well characterized for its role in proteostasis, it is also known to regulate chromosome architecture in the oocyte during meiosis. This proposal will investigate how oocyte intrinsic HSF1 activity and maternal gestational stress influence fetal oocyte development. By using genetic mouse models, in vivo models of increased GR activity, whole ovary clearing, three-dimensional imaging, and quantitative analysis, this proposal will (1) establish a comprehensive, three-dimensional spatiotemporal map of HSF1 expression, localization, and activity in the fetal ovary and test whether HSF1 plays a germ cell-intrinsic role in embryonic meiosis and (2) identify the relationship between GR and Hsf1 in the fetal oocyte and the consequences for both embryonic meiosis and oocyte growth and maturation. Improving our limited understanding of the long-term consequences of global increased GR activity on the developing germline is crucial as the potent pharmacological agonist of GR, dexamethasone, is routinely administered during pregnancy to stimulate lung maturation when premature birth is a concern. Additionally, elucidating the mechanistic effects of physiological stress in the oocyte will support our understanding of the consequences for vulnerable populations who have a higher risk of exposure to stress- inducing environmental and socioeconomic conditions. To successfully complete the work outlined in this F31 proposal and to achieve my career goals, I have chosen to perform the proposed work in the laboratory of my Sponsor, Dr. Diana Laird, at the University of California, San Francisco. The complementary expertise of my Co-Sponsor, Dr. Marco Conti, and Collaborator, Dr. Aditi Bhargava, as well as the support provided by this F31 Fellowship assure I will receive the technical training and mentorship to complete my pre-doctoral research and contribute to the field of reproductive biology.