Paxillin and Androgens in the Regulation of Ovarian Follicle Development

桩蛋白和雄激素在卵巢卵泡发育调节中的作用

基本信息

批准号：
10688086
负责人：
Olga Igor Astapova
金额：
$ 15.87万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688086
关键词：
Adaptor Signaling Protein Advisory Committees Affect Androgen Receptor Androgens Anovulation Apoptosis Apoptotic Biology Cell Proliferation Cells Chronic Communities Cytoplasm Data Development Disease Doctor of Philosophy Enterobacteria phage P1 Cre recombinase Equilibrium Estrous Cycle Failure Female Female infertility Fertility Follicular Atresia Gene Targeting Genetic Transcription Grant Grooming Growth Hormone imbalance Hour Human Infertility Instruction Knock-out Knockout Mice Laboratories Leadership Ligands Litter Size Malignant neoplasm of prostate Mediating Mediator Mentors Messenger RNA MicroRNAs Molecular Mullerian-inhibiting substance receptor Mus Nuclear Translocation Ovarian Ovarian Follicle Ovarian hormone Ovary Ovulation Pathway interactions Patients Phenotype Physicians Pilot Projects Polycystic Ovary Syndrome Post-Transcriptional Regulation Protein Synthesis Inhibition Proteins Psyche structure Public Health Publications Qualifying Regulation Reproduction Reproductive Sciences Research Research Methodology Research Personnel Research Technics Role Running Scientist Signal Transduction Small RNA Steroids Supplementation Technical Expertise Time Training Translational Research Translations Universities Untranslated RNA Writing androgen excess career career development collaborative environment cost design diminished ovarian reserve female fertility folliculogenesis follow-up graduate student granulosa cell improved inhibitor interest knock-down mRNA Expression mRNA sequencing male fertility meetings member miRNA expression profiling mouse genetics mouse model multicatalytic endopeptidase complex mutant novel novel therapeutics paxillin promoter protein degradation receptor expression reproductive small molecule stem therapeutic candidate transcriptome

项目摘要

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.

1个项目摘要 /摘要 2这个职业发展项目将为拥有合并的MD/PHD的高素质候选人提供一条途径在生殖科学领域的独立研究者中，职业生涯有3个学位。女性不育症引起的疾病雄激素超过或不足的4是美国的日益严重的问题，精神和财务高 5费用。多囊卵巢综合征（PCOS）暗示雄激素失衡，卵巢储备减少 6（dor）;但是，尽管雄激素活性在卵巢中的表型作用很重要，但鲜为人知 7关于基础分子途径。该建议旨在阐明雄激素作用的机制 8在卵泡卵泡生长和闭锁中，它们在PCOS和DOR中无序。研究方向步骤 9从候选人最近的发现，雄激素调节的mRNA转录组在卵巢颗粒中 10个细胞非常小，专注于颗粒细胞中雄激素的非编码RNA调节。这 11提案还基于对帕克西林作为前列腺癌中雄激素信号传导的介体的先前研究。角色帕克西林的第12个作为雄激素受体表达的调节剂，首次在颗粒细胞中评估 13这个建议。将检查帕西林损失在颗粒细胞中对卵泡发育和生育能力的影响 14在颗粒细胞特异性敲除小鼠模型中。涉及microRNA调节的分子机制 15颗粒细胞中的雄激素将在培养的小鼠和人类细胞中研究。假设是 16颗粒细胞中的雄激素作用在很大程度上由microRNA介导，并通过帕西林增强。这 17项目有可能提出针对PCOS的新型热途径，PCOS是一种优化的疾病 18种管理选项。培训计划利用申请人的强大研究背景和长期 19对女性生育的兴趣。她的目标是基于自己的技术技能，发展成领导者和成员科学界的20个，并过渡到研究中的独立性。心理是一个身体科学家 21是Paxillin和雄激素信号，小鼠遗传学和卵巢生物学的世界专家 22名心理成功的学员。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。申请人已组建一个咨询委员会 24完成了世界卵巢生物学，帕克西林，类固醇信号传导和microRNA测序的世界专家。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，以及研究中心，国家会议和一对一指导。最后 27项目，她计划撰写几本第一任作者出版物，独立运行一个实验室，精神上的研究生 28并申请R-01赠款。