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：
10640129
负责人：
JoAnne Stewart Richards
金额：
$ 32.78万
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/10640129
关键词：
Aging Androgen Receptor Androgens Apoptosis Appearance Binding Blood Vessels CYP17A1 gene Cell Adhesion Cell Separation 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 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 cell stroma chicken ovalbumin upstream promoter-transcription factor 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.

项目摘要我们的新研究表明，雄激素受体（AR）和AR作用共抑制剂的调节剂 couptf-ii/nr2f2在小鼠卵巢卵泡的theca细胞和正常细胞中共表达骑自行车和PCOS患者。小鼠暴露于体内的雄激素导致theca细胞的明显变化形态和基因表达谱，其中最值得注意的是血管细胞的明显诱导粘附分子1（VCAM1）。最近的挑衅性证据表明，小鼠theca中AR的破坏细胞防止雄激素介导的PCOS表型，VCAM1的诱导为 AR在theca细胞中的关键作用。来自PCOS女性传播的theca细胞表达了更高水平的 VCAM1和CYP17A1比正常的theca细胞，进一步支持了升高VCAM1和雄激素会导致PCOS和过度症的卵巢功能和功能障碍的改变。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theca细胞的AR调节功能导致细胞和分子事件的特定变化，包括诱导VCAM1的诱导基础和/或导致PCOS和多重症的卵巢功能障碍。我们建议在遗传上使用改良的小鼠模型，从正常循环和PCOS卵巢中分离出的theca细胞以及最新的分子和细胞技术实现三个特定目标。特定目标1：确定破坏AR，NR2F2或VCAM1的细胞和分子后果从正常循环和 PCOS妇女文化中。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theca/stromal中有选择性表达时发生的变化细胞。特定目标3：确定雄激素在theca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提供关键的新见解。通过确定哪些细胞事件和分子途径有选择性改变，影响卵巢功能障碍在theca细胞中，通过不同水平的AR受体激活。通过结合强大的突变鼠标模型和特征良好的人类theca细胞，调节雄激素作用的新策略以及将建立女性的雄激素过量，并提供新颖的诊断标记和治疗性 PCOS和性超死的靶标。