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Progesterone regulation of human luteal cell viability

黄体酮对人黄体细胞活力的调节

基本信息

批准号：
7076218
负责人：
JOHN J PELUSO
金额：
$ 7.23万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-10 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7076218
关键词：
apoptosis cell differentiation chorionic gonadotropin corpus luteum female genetic regulation granulosa cell hormone regulation /control mechanism human tissue immunocytochemistry polymerase chain reaction progesterone progesterone receptors receptor expression secretion single cell analysis small interfering RNA tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): Both nuclear progesterone receptors (nPRs), PR-A and PR-B, are expressed in human luteal cells. Further, progesterone (P4) inhibits and the nPR antagonist, RU486, induces human luteal cell apoptosis (i.e., programmed cell death). These observations suggest that P4 mediates its antiapoptotic action by activating the nPRs. However, recent studies have shown that P4 modulates luteal cell function by both genomic and non-genomic mechanisms. Moreover, several membrane receptors, or mediators of P4's action, are expressed by luteal cells. Since the precise regulation of luteal cell viability is required for the reproductive process, it is essential that we determine which receptor, or receptors, mediates P4's antiapoptotic action in human luteal cells. We should not accept the concept that P4 mediates its antiapoptotic action exclusively through the nPRs, since this assumption is based solely on nPR expression and pharmacological studies. Therefore, we will use genetic approaches to modulate the levels of nPRs in cultured human luteal cells and then assess P4's ability to prevent luteal cell apoptosis. We propose the following three specific aims: 1) to characterize human luteal cell differentiation and regression in vitro in terms of P4 secretion and expression of nPR as well as other potential mediators of P4's action; 2) to correlate the ability of P4 to maintain the viability of human luteal cells with the expression of the nPRs and other P4 mediators; and 3) to determine the effect of specific ablation and over expression of the nPRs on the ability of P4 to promote luteal cell viability. If the studies indicate that P4's antiapoptotic activity is not exclusively mediated by the nPRs, then one or more of the other potential P4 mediators could be involved in transducing P4's antiapoptotic action. If so, this could open up new areas of pharmacology that would be directed toward inhibiting or enhancing the action of these other P4 mediators. Since the structures of three of these candidate proteins are very different from that of the nPRs, drugs could potentially be developed that influence their action without interfering with the action of the nPRs. Such selective manipulation of the P4's actions could have far reaching effects on the treatment for infertility, contraception and certain types of cancers.

描述（由申请人提供）：核孕酮受体（nPR）PR-A和PR-B均在人黄体细胞中表达。此外，孕酮（P4）抑制并且nPR拮抗剂RU 486诱导人黄体细胞凋亡（即，程序性细胞死亡）。这些观察结果表明，P4介导的抗凋亡作用，通过激活nPR。然而，最近的研究表明，P4通过基因组和非基因组机制调节黄体细胞功能。此外，一些膜受体，或P4的作用介质，由黄体细胞表达。由于精确调节黄体细胞的活力是需要的生殖过程中，这是至关重要的，我们确定哪些受体，或受体，介导P4的抗凋亡作用在人类黄体细胞。我们不应该接受P4完全通过nPR介导其抗凋亡作用的概念，因为这种假设仅仅基于nPR表达和药理学研究。因此，我们将使用遗传方法来调节培养的人黄体细胞中nPR的水平，然后评估P4预防黄体细胞凋亡的能力。我们提出了以下三个具体目标：1）从P4分泌和nPR表达以及P4作用的其他潜在介质方面来表征体外人黄体细胞分化和退化; 2）将P4维持人黄体细胞活力的能力与nPR和其他P4介质的表达相关联;和3）确定特异性消融和nPR的过表达对P4促进黄体细胞活力的能力的影响。如果研究表明P4的抗凋亡活性不完全由nPR介导，那么一种或多种其他潜在的P4介质可能参与转导P4的抗凋亡作用。如果是这样的话，这可能会开辟新的药理学领域，将直接抑制或增强这些其他P4介质的作用。由于这些候选蛋白质中的三种的结构与nPR的结构非常不同，因此可能会开发出影响其作用而不干扰nPR作用的药物。这种对P4作用的选择性操纵可能对不孕症、避孕和某些类型的癌症的治疗产生深远的影响。