17 alpha-Hydroxylase Expression in Human Ovarian Cells

17 α-羟化酶在人卵巢细胞中的表达

基本信息

批准号：
7222639
负责人：
Jan M McAllister
金额：
$ 26.57万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7222639
关键词：
Abbreviations Adenoviruses Affect Anabolism Androgens Area CYP11A1 gene Cell physiology Cells Cholesterol Cholesterol Monooxygenase (Side-Chain-Cleaving)Cytochrome P450 Data Defect Development Dominant-Negative Mutation Dose Event Follicular Fluid Funding Gene Expression Genetic Transcription Goals Human Infection Laboratories Lead Lesion Literature MAP2K1 gene MAP3K1 gene MAPK14 gene MEKKs Messenger RNA Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Mixed Function Oxygenases Molecular Motion Ovarian Ovary Pathway interactions Phenotype Phosphotransferases Plasma Polycystic Ovary Syndrome Production Regulation Reporting Research Design Resistance Side Signal Pathway Signal Transduction Steroid 17-alpha-monooxygenase Stream System Testing Theca folliculi structure Transcriptional Regulation Tumor Necrosis Factor-alpha Tumor Necrosis Factors Woman base dehydroepiandrosterone design human TNF protein insight mRNA Stability novel promoter receptor research study response theca cell tool

项目摘要

DESCRIPTION (provided by applicant): The proposed experiments are designed to elucidate the regulatory mechanisms underlying androgen biosynthesis in theca interna cells from ovaries of normal cycling women and women with polycystic ovary syndrome (PCOS). During the past funding period, we obtained exciting data demonstrating that increased androgen production and augmented P450 17alpha-hydroxylase (CYP17) gene expression in PCOS theca cells results from a combined reduction in the activation state of the MEK1/ERK pathway and a stimulation in the activation state of the MKK3 pathway. We have observed that infection of normal theca cells with adenovirus expressing dominant negative MEK1 and constitutively active MKK3 recapitulates a PCOS theca cell phenotype. We now have the tools to fully explore the contributions of the other components of the MAPK signaling pathways. In this proposal we will test the hypothesis that increased ovarian androgen production is a consequence of altered mitogen activated protein kinase (MAPK) signaling in PCOS theca cells. Aim 1 studies are designed to investigate whether dysregulation of upstream signaling component(s) of the ERK and p38 signaling pathway(s) (i.e., Raf-1, MEKK1, MEKK3) directly affect the down stream signaling components of each homologous pathway to the extent that CYP17 and CYP11A1 gene expression, and androgen biosynthesis are up-regulated in PCOS theca cells. We will also examine whether dysregulation of signaling components from one pathway result(s) in compensatory changes in signaling through parallel pathway(s). In Aim 2 we will investigate the extent to which alterations in ERK and p38 signaling contribute to increased CYP17 and CYP11A1 gene transcription and mRNA stability in PCOS theca cells. Throughout the literature there are data to support that tumor necrosis factor a (TNF) inhibits thecal CYP17 gene expression and androgen biosynthesis. However, these data are contradictory with the observation that PCOS women have elevated circulating plasma and follicular fluid levels of TNF. In Aim 3, we will examine the extent to which defects in MAPK signaling in PCOS theca cells affects TNF-dependent regulation of androgen biosynthesis. Results of these studies will provide both new insights regarding the cause and molecular basis for increased ovarian androgen production, and lead to the development of new targets for treatment of women with PCOS.

描述（由申请人提供）：拟议的实验旨在阐明来自正常循环妇女和多囊卵巢综合征（PCOS）的卵巢中theca Interna细胞中雄激素生物合成的调节机制。在过去的资金期间，我们获得了令人兴奋的数据，该数据表明，PCOS theca细胞中雄激素产生和增强的P450 17Alpha-Hydroxylase（CYP17）基因表达是由MEK1/ERK途径的激活状态综合降低而导致的，而MKK3途径的激活状态刺激了。我们已经观察到，正常theca细胞用腺病毒表达显性负MEK1并组成活性MKK3的感染会概括PCOS theca细胞表型。现在，我们拥有完全探索MAPK信号通路其他组件的贡献的工具。在此提案中，我们将检验以下假设：卵巢雄激素的产生增加是PCOS THECA细胞中有丝分裂原活化蛋白激酶（MAPK）信号改变的结果。 AIM 1研究旨在研究ERK和p38信号通路上游信号传导成分的失调（即RAF-1，MEKK1，MEKK3）是否直接影响CYP17和CYP11A1和CYP11A1 GENE CENSERIS的每个同源途径的下流信号传导成分。我们还将检查在通过平行途径的信号变化中，是否从一个途径结果（s）中的信号传导失调。在AIM 2中，我们将研究ERK和p38信号传导的改变有助于增加CYP17和CYP11A1基因转录以及PCOS THECA细胞中的mRNA稳定性。在整个文献中，有数据支持肿瘤坏死因子A（TNF）抑制thecal CYP17基因表达和雄激素生物合成。但是，这些数据与观察到PCOS妇女的血浆和滤泡流体水平升高的观察结果是矛盾的。在AIM 3中，我们将研究PCOS theca细胞中MAPK信号传导中缺陷的程度影响雄激素生物合成的TNF依赖性调节。这些研究的结果将提供有关增加卵巢雄激素产生的原因和分子基础的新见解，并导致开发用于治疗PCOS女性的新目标。