Novel Aspect of Androgen Action in Ovarian Cell Function and Dysfunction

项目摘要 我们的新研究表明，雄激素受体（AR）和AR作用的调节因子共阻遏物， COUPTF-II/NR2F2在小鼠卵泡膜细胞和正常人卵泡膜细胞中共表达 骑自行车和PCOS患者。小鼠体内暴露于雄激素导致卵泡膜细胞的显著变化 形态学和基因表达谱，其中最显著的是血管细胞的显著诱导， 粘附分子1（Vcam 1）。最近的挑衅性证据表明，在小鼠卵泡膜中选择性地破坏AR， 细胞阻止雄激素介导的PCOS表型，Vcam1的诱导为 AR在卵泡膜细胞中的重要作用。从PCOS妇女繁殖的卵泡膜细胞表达更高水平的 与正常卵泡膜细胞相比，VCAM 1和CYP17A1升高，进一步支持了VCAM 1和CYP17A1升高的观点。 雄激素导致PCOS和卵泡膜增生症中卵巢功能改变和功能障碍。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异性变化的功能，包括诱导Vcam 1， 是PCOS和卵泡膜增生症中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卵巢分离的卵泡膜细胞，以及最先进的 分子和细胞技术，以实现三个具体目标。 具体目标1：确定破坏Ar、Nr2f2或Vcam 1的细胞和分子后果 选择性地在体内小鼠卵泡膜/基质细胞中和在来自正常循环的人卵泡膜细胞中， PCOS女性文化 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Vcam 1在小鼠和人卵泡膜/基质中选择性过表达时， 细胞 具体目标3：确定雄激素诱导卵泡膜细胞中Vcam 1的分子机制 如果炎症因子和细胞是VCAM 1表达的关键， 这些研究的结果将为雄激素、AR、NR2F2和VCAM 1 通过确定哪些细胞事件和分子途径被选择性改变来影响卵巢功能障碍 在卵泡膜细胞中通过不同水平的AR受体激活。通过结合强大的突变小鼠模型和 充分表征的人类卵泡膜细胞，调节雄激素作用的新策略以及 将建立女性雄激素过多，并提供新的诊断标志物和治疗方法。 多囊卵巢综合征和卵泡膜增生症的治疗目标。

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.