Integration of PR and FoxO Signaling in Pituitary Gonadotropes

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DESCRIPTION (provided by applicant): This application for a Mentored Research Scientist Development Award outlines the training and research plans for Dr. Varykina Thackray. She has designed an integrated and intensive training program in the area of hormonal regulation of LH and FSH. Metabolic disorders characterized by hyperinsulinemia and insulin resistance are often associated with reduced fertility in women. Since the pituitary gonadotrope integrates signals from multiple external stimuli, she proposes to study whether metabolism and fertility are connected at this level by integration of progesterone receptor (PR) and forkhead (FoxO) signaling. The proposed work and unique training environment at the University of California, San Diego will allow Dr. Thackray to achieve her long-term goal of a fully independent research career in the field of reproductive endocrinology. Training and development will entail mentoring by Dr. Pamela Mellon and Dr. Karen Arden, noted experts in the fields of neuroendocrinology and FoxO regulation and function, respectively. Dr. Thackray's participation in UCSD's Department of Reproductive Medicine and the Center for Reproductive Science and Medicine will augment both her research and career development. The research component of the proposal tests the hypothesis that PR engages in cross-talk with FoxO transcription factors to modulate the transcriptional program of the gonadotrope including LH and FSH synthesis. In her post-doctoral work, Dr. Thackray has shown that PR modulates LH and FSH beta gene expression in the pituitary gonadotrope and that PR interacts with transcription factors intermediates in peptide hormone signaling pathways such as Smad and FoxO proteins. Her preliminary results indicate that FoxO proteins play a direct role in gonadotropin synthesis and enhance PR responsiveness. In Specific Aim 1, biochemical and tissue cell culture models will be used to study the role of the FoxO1 transcription factor in the regulation of gonadotropin production. In Specific Aim 2, comprehension of FoxO1 function in the pituitary gonadotrope will be expanded using genetic analysis of conditional null FoxO1 mice to study its function in vivo and Specific Aim 3 will address PR and FoxO cross-talk in the gonadotrope using genome wide location analysis to identify co-regulated PR and FoxO1 target genes. Results from this proposal have the potential to answer fundamental questions regarding the role of PR and FoxO transcription factors in gonadotropin production, provide insight into broad mechanisms of hormonal control of fertility, and allow the candidate to develop into an fully independent principal investigator. Potential applications could lead to new directions in treating a range of physiological disorders that can result from malfunction in gonadotropin production such as amenorrhea, precocious puberty, ideopathic hypogonadism, polycystic ovarian syndrome and infertility.