1 Project Summary / Abstract 2 This career development project will provide a path for a highly qualified candidate with a combined MD/PhD 3 degree into a career as an independent investigator in reproductive science. Female infertility due to disorders 4 of androgen excess or insufficiency is a growing problem in the U.S. and worldwide with high mental and financial 5 costs. Androgen imbalance is implicated in polycystic ovary syndrome (PCOS) and diminished ovarian reserve 6 (DOR); however, while the phenotypic effects of androgen activity in the ovary are significant, little is known 7 about the underlying molecular pathways. This proposal aims to elucidate the mechanisms of androgen actions 8 in ovarian follicle growth and atresia, which are disordered in PCOS and DOR. The research direction stems 9 from the recent finding by the candidate that the androgen-regulated mRNA transcriptome in ovarian granulosa 10 cells is surprisingly small, and focuses on non-coding RNA regulation by androgens in granulosa cells. The 11 proposal also builds on prior studies of paxillin as a mediator of androgen signaling in prostate cancer. The role 12 of paxillin as a regulator of the androgen receptor expression is assessed for the first time in granulosa cells in 13 this proposal. The effects of paxillin loss in granulosa cells on follicular development and fertility will be examined 14 in a granulosa cell-specific knockout mouse model. The molecular mechanisms involving microRNA regulation 15 by androgens in granulosa cells will be studied in cultured mouse and human cells. The hypothesis is that 16 androgen effects in granulosa cells are mediated in large part by microRNAs, and are enhanced by paxillin. The 17 project has the potential to suggest novel therapeutic avenues for PCOS, a disease with sub-optimal 18 management options. The training plan capitalizes on the applicant’s strong research background and long- 19 standing interest in female fertility. She aims to build on her technical skills, develop as a leader and a member 20 of the scientific community, and transition to independence in research. The mentor is a physician-scientist who 21 is a world expert in paxillin and androgen signaling, mouse genetics and ovarian biology with a long track record 22 of mentoring successful trainees. The training will take place in a highly collaborative environment where 23 expertise in reproductive research techniques is abundant. The applicant has assembled an advisory committee 24 comprised of world experts in ovarian biology, paxillin, steroid signaling, and microRNA sequencing. She will 25 take advantage of University-sponsored courses in translational research methods, leadership and professional 26 development, as well as research seminars, national meetings and one-on-one instruction. At the end of this 27 project, she plans to write several first-author publications, run a lab independently, mentor a graduate student 28 and apply for an R-01 grant.

Project Narrative Female infertility due to disorders of androgen imbalance, namely polycystic ovary syndrome and ovarian insufficiency, are a growing public health problem in the U.S. and worldwide. This project aims to delineate the mechanisms of androgen actions in the ovary, focusing on novel non-coding RNA regulation by androgen receptor in granulosa cells and the role of cytoplasmic adaptor protein paxillin. The training plan is designed to groom a young physician-scientist for an independent career in reproductive science, and the findings will advance our understanding of the molecular mechanisms underlying female fertility.