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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.

项目概要我们的新研究表明，雄激素受体 (AR) 和 AR 作用的调节剂共阻遏物 COUPTF-II/NR2F2 在小鼠卵泡和正常卵泡膜细胞中共表达骑自行车和多囊卵巢综合症患者。小鼠体内暴露于雄激素会导致卵泡膜细胞发生显着变化形态和基因表达谱，其中最值得注意的是血管细胞的显着诱导粘附分子 1 (Vcam1)。最近的挑衅性证据表明 AR 在小鼠卵泡膜中选择性破坏细胞可预防雄激素介导的 PCOS 表型，而 Vcam1 的诱导提供了关键证据 AR 在卵泡膜细胞中的关键作用。从 PCOS 女性中繁殖的卵泡膜细胞表达更高水平的 VCAM1 和 CYP17A1 高于正常卵泡膜细胞，进一步支持了 VCAM1 和 CYP17A1 升高的观点雄激素会导致卵巢功能改变以及多囊卵巢综合征和卵泡细胞增多症的功能障碍。基于这些令人信服的观察结果，我们假设升高的雄激素改变了卵泡膜细胞的 AR 调节导致细胞和分子事件发生特定变化的功能，包括 Vcam1 的诱导，是 PCOS 和卵泡细胞增多症卵巢功能障碍的基础和/或促成因素。我们建议使用基因- 改良的小鼠模型，从正常周期和 PCOS 卵巢中分离出的卵泡膜细胞，以及最先进的分子和细胞技术来实现三个具体目标。具体目标 1：确定破坏 Ar、Nr2f2 或 Vcam1 的细胞和分子后果选择性地在小鼠体内的卵泡膜/基质细胞和来自正常循环和的人类卵泡膜细胞中文化中的多囊卵巢综合症女性。具体目标 2：确定分子和细胞事件以及对雄激素的反应当 AR、NR2f2 或 Vcam1 在小鼠和人类卵泡膜/基质中选择性过度表达时发生改变细胞。具体目标 3：确定雄激素在卵泡膜细胞中诱导 Vcam1 的分子机制如果炎症因子和细胞对于 VCAM1 表达至关重要这些研究的结果将为雄激素、AR、NR2F2 和 VCAM1 如何发挥作用提供重要的新见解通过确定选择性改变哪些细胞事件和分子途径来影响卵巢功能障碍在卵泡膜细胞中被不同水平的AR受体激活。通过结合强大的突变小鼠模型和特征明确的人类卵泡膜细胞、调节雄激素作用的新策略以及其后果将确定女性雄激素过多并提供新的诊断标记和治疗方法 PCOS 和卵泡细胞增多症的目标。