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PROGESTERONE RECEPTOR GENE REGULATION IN THE RAT OVARY

大鼠卵巢中孕酮受体基因的调控

基本信息

批准号：
2673723
负责人：
Ok-Kyong Park-Sarge
金额：
$ 10.7万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2000-04-30
项目状态：
已结题

项目摘要

The long-term objective of the present proposal is to understand how progestins regulate the female reproductive axis, with particular emphasis on progesterone receptor (PR) gene regulation in ovarian granulosa cells. Progestins have been proposed to affect many aspects of ovarian function and to participate in the normal process of ovulation and/or luteinization of the follicle. We hypothesized that an intracellular PR molecule may mediate progesterone action in the ovary and therefore, isolated the rat PR cDNA and genomic clones to initiate a multifaceted approach to study the expression and regulation of ovarian PRs. Our preliminary results demonstrating transient PR gene expression in the granulosa cells of preovulatory follicles during the periovulatory period strongly suggest the potential involvement of PRs for mammalian ovulation. The regulatory mechanisms for PR gene expression in these cells appear to be quite different from other progesterone-responsive cells, because gonadotropins, but not estrogen, directly induce PR gene expression in rat granulosa cells. This gonadotropin-induced PR gene expression in ovarian granulosa cells is likely to be mediated by a cAMP- mediated pathway, at least in part, at the level of transcription. Our preliminary results also suggest the likely involvement of protein kinase C in PR gene regulation in ovarian granulosa cells. The central hypothesis in this proposal, then, is that the PR gene in ovarian granulosa cells is regulated predominantly by G protein-coupled signaling pathways, for example cAMP- and DAG-dependent pathways. We now propose to extend our preliminary studies to investigate the cellular and molecular mechanisms by which the PR gene is regulated in rat ovarian granulosa cells. The first goal of this proposal is to examine intracellular signaling pathways which are directly involved in PR gene expression in ovarian granulosa cells; - our studies will focus on protein kinases A and C. The second goal of this proposal is to identify and characterize the cis-DNA regulatory elements mediating the activation of the PR gene by these intracellular signaling pathways; our studies will focus on cAMP- or TPA-induced expression of the PR gene. The final goal of this proposal is to examine the potential role of estrogen in PR gene expression in rat granulosa cells; we will determine the capacity of ovarian granulosa cells in mediating estrogen-induced signals. We expect these experiments to enhance our understanding of PR regulation and function for the process of ovulation and/or luteinization in the mammalian ovary and to provide a framework for determining whether alterations in PR function might participate in reproductive diseases or dysfunction.

本提案的长期目标是了解如何孕激素调节女性生殖轴，特别是孕激素受体（PR）基因调控在卵巢癌中的作用颗粒细胞孕激素已被提出影响许多方面，卵巢功能和参与正常的排卵过程和/或卵泡的黄体化。我们假设细胞内PR分子可能介导卵巢中孕酮的作用因此，分离大鼠PR cDNA和基因组克隆，多方面的方法来研究卵巢癌的表达和调节，公关。我们的初步结果表明瞬时PR基因表达在排卵前卵泡的颗粒细胞中，时期强烈表明PR可能参与哺乳动物排卵PR基因表达的调控机制在这些细胞似乎与其他对孕酮敏感的细胞完全不同，细胞，因为促性腺激素，而不是雌激素，直接诱导PR基因在大鼠颗粒细胞中的表达。这个促性腺激素诱导的PR基因在卵巢颗粒细胞中的表达可能是由cAMP介导的，介导的途径，至少部分，在转录水平。我们初步结果还表明，蛋白激酶可能参与 C在卵巢颗粒细胞PR基因调控中的作用这个提议的核心假设是，卵巢颗粒细胞主要由G蛋白偶联的信号传导途径，例如cAMP和DAG依赖性途径。我们现在我建议扩大我们的初步研究，以调查细胞和大鼠卵巢中PR基因调控的分子机制颗粒细胞这项提案的第一个目标是审查 PR基因直接参与的细胞内信号通路表达在卵巢颗粒细胞; -我们的研究将集中在蛋白激酶A和C。该提案的第二个目标是确定并表征介导激活的顺式DNA调控元件 PR基因的细胞内信号通路;我们的研究将集中在cAMP或TPA诱导的PR基因表达。最终这项提案的目的是研究雌激素在PR中的潜在作用，大鼠颗粒细胞中的基因表达;我们将确定卵巢颗粒细胞介导雌激素诱导的信号。我们我希望这些实验能增强我们对PR调节的理解和功能的排卵和/或黄体化的过程中，哺乳动物卵巢，并提供一个框架，以确定是否 PR功能的改变可能参与生殖疾病或功能障碍