权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel Aspect of Androgen Action in Ovarian Cell Function and Dysfunction

雄激素在卵巢细胞功能和功能障碍中作用的新方面

基本信息

批准号：
10415947
负责人：
JoAnne Stewart Richards
金额：
$ 32.72万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415947
关键词：
Aging Androgen Receptor Androgens Apoptosis Appearance Binding Blood Vessels CYP17A1 gene Cell Adhesion Cell Survival Cell physiology Cells Cellular Morphology Data Development ESR1 gene ESR2 gene Embryo Endometrioid Carcinoma Estradiol Estrogen Receptors Event Female Fertility Functional disorder Gene Expression Genes Gonadal structure Growth Human Hyperplasia Impairment In Vitro Inflammatory Knockout Mice Lead Masculine Mediating Molecular Morphology Mus Mutation Ovarian Ovarian Follicle Ovary Ovulation Pathway interactions Patients Phenotype Play Polycystic Ovary Syndrome Process Production Receptor Activation Receptor Signaling Regulation Role Serum Stromal Cells Structure Technology Testis Testosterone Theca folliculi structure Tissues Uterine Polyp Virilism Woman androgen excess apoAI regulatory protein-1 base cell stroma diagnostic biomarker female fertility fetal genetic corepressor granulosa cell hyperthecosis in vivo innovation insight intraovarian mouse model mutant mouse model novel novel diagnostics novel therapeutics ovarian dysfunction overexpression prevent reproductive response theca cell therapeutic target

项目摘要

Project Summary Our novel studies show that the androgen receptor (AR) and the modulator of AR action co-repressor COUPTF-II/NR2F2 are co-expressed in theca cells of mouse ovarian follicles and in theca cells of normal cycling and PCOS patients. Exposure of mice to androgens in vivo leads to marked changes in theca cell morphology and gene expression profiles, most notable of which is the marked induction of vascular cell adhesion molecular 1 (Vcam1). Recent provocative evidence that disruption of AR selectively in mouse theca cells prevents an androgen-mediated PCOS phenotype and the induction of Vcam1 provides key evidence for critical actions of AR in theca cells. Theca cells propagated from PCOS women express higher levels of VCAM1 and CYP17A1 than normal theca cells, further supporting the notion that elevated VCAM1 and androgens contribute to altered ovarian functions and dysfunctions in PCOS and hyperthecosis. Based on these compelling observations, we hypothesize that elevated androgens alter AR regulation of theca cell functions leading to specific changes in cellular and molecular events, including the induction of Vcam1, that underlie and/or contribute to ovarian dysfunction in PCOS and hyperthecosis. We propose to use genetically- modified mouse models, theca cells isolated from normal cycling and PCOS ovaries, and state-of-the-art molecular and cellular technologies to accomplish three Specific Aims. Specific Aim 1: Determine the cellular and molecular consequences of disrupting Ar, Nr2f2 or Vcam1 selectively in the mouse theca/stromal cells in vivo and in human theca cells from normal cycling and PCOS women in culture. Specific Aim 2: Determine the molecular and cellular events and responses to androgens that are altered when AR, NR2f2 or Vcam1 is selectively over-expressed in mouse and human theca/stromal cells. Specific Aim 3: Determine the molecular mechanisms by which androgens induce Vcam1 in theca cells and if inflammatory factors and cells are theca critical for VCAM1 expression Results of these studies will provide key new insights into how androgens, AR, NR2F2 and VCAM1 impact ovarian dysfunction by determining what cellular events and molecular pathways are altered selectively in theca cells by different levels of AR receptor activation. By combining powerful mutant mouse models and well-characterized human theca cells, new strategies for regulating androgen action and the consequences of androgen excess in women will be established and provide for novel diagnostic markers and therapeutic targets for PCOS and hyperthecosis.

项目总结