Paxillin and Androgens in the Regulation of Ovarian Follicle Development

1项目摘要/摘要 这一职业发展项目将为拥有医学博士学位的高资质候选人提供一条道路 3学位，成为一名生殖科学的独立研究员。女性疾患所致不孕 雄激素过剩或不足在美国和世界范围内是一个日益严重的问题，精神和经济状况都很高 5个成本。雄激素失衡与多囊卵巢综合征(PCOS)和卵巢储备减少有关 6(DOR)；然而，尽管卵巢中雄激素活性的表型效应是显著的，但鲜为人知 7关于潜在的分子途径。这项建议旨在阐明雄激素的作用机制。 8卵泡生长和闭锁，在PCOS和DOR中表现为紊乱。本论文的研究方向是 9来自候选人最近发现的卵巢颗粒中雄激素调节的mRNA转录组 10细胞小得令人惊讶，它专注于颗粒细胞中雄激素对非编码RNA的调节。这个 11提案还建立在之前关于帕西林作为前列腺癌雄激素信号媒介的研究基础上。角色 12帕西林作为雄激素受体表达的调节剂首次在卵巢颗粒细胞中被评估。 13.这项建议。我们将研究颗粒细胞中的巴西林丢失对卵泡发育和生育的影响。 14在颗粒细胞特异性基因敲除小鼠模型中表达。MicroRNA调控的分子机制 15颗粒细胞中的雄激素将在培养的小鼠和人类细胞中进行研究。假设是这样的 颗粒细胞中的雄激素效应在很大程度上是由microRNAs介导的，并被巴西林增强。这个 17项目有可能为多囊卵巢综合征提供新的治疗途径，这是一种次优疾病 18个管理选项。该培训计划充分利用了申请者雄厚的研究背景和长期的 19.对女性生育能力的长期关注。她的目标是在自己的技术技能基础上，发展成为领导者和成员 科学界的20人，并在研究方面向独立过渡。导师是一位内科科学家，他 21岁是帕克西林和雄激素信号、小鼠遗传学和卵巢生物学方面的世界专家，有着长期的记录 指导成功学员的比例为22%。培训将在高度协作的环境中进行， 23生殖研究技术方面的专业知识丰富。申请人已经组建了一个咨询委员会 24由卵巢生物学、帕克西林、类固醇信号和microRNA测序方面的世界专家组成。她会的 25利用大学赞助的翻译研究方法、领导力和专业课程 26发展，以及研究研讨会、国家会议和一对一指导。在这个结束的时候 27项目，她计划写几本第一作者的出版物，独立运营一个实验室，指导一名研究生 28，并申请R-01拨款。

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.