Progesterone regulation of human luteal cell viability

黄体酮对人黄体细胞活力的调节

• 批准号: 6954295
• 负责人: JOHN J PELUSO
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954295
• 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

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（NPRS），PR-A和PR-B在人的黄体细胞中均表达。此外，孕酮（P4）抑制了NPR拮抗剂RU486，诱导人类黄体细胞凋亡（即程序性细胞死亡）。这些观察结果表明，P4通过激活NPR介导其抗凋亡作用。但是，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，黄体细胞表达了几种膜受体或P4作用的介体。由于生殖过程需要精确调节黄体细胞活力，因此我们必须确定哪种受体或受体会介导P4在人类黄体细胞中的抗凋亡作用。我们不应该接受P4仅通过NPR介导其抗凋亡作用的概念，因为该假设仅基于NPR表达和药理研究。因此，我们将使用遗传方法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。我们提出以下三个具体目的：1）在NPR的P4分泌和表达以及P4作用的其他潜在介体方面，体外表征人类黄体细胞分化和回归； 2）将P4维持人黄体细胞生存能力的能力与NPRS和其他P4介质的表达相关联； 3）确定特异性消融和NPR的表达对P4促进黄体细胞活力的能力的影响。如果研究表明P4的抗凋亡活性不仅是由NPRS介导的，那么其他潜在的P4介质中的一个或多个可能与P4的抗凋亡作用有关。如果是这样，这可能会开辟新的药理学领域，这些领域将致力于抑制或增强这些其他P4介体的作用。由于这些候选蛋白中的三种结构与NPR的结构有很大不同，因此可能会开发出可能影响其作用的药物而不会干扰NPR的作用。这种对P4行为的选择性操纵可能会对不育，避孕和某些类型的癌症的治疗产生巨大影响。