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（nPR）PR-A 和 PR-B 均在人黄体细胞中表达。此外，黄体酮 (P4) 会抑制人黄体细胞凋亡，而 nPR 拮抗剂 RU486 会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 通过激活 nPR 介导其抗凋亡作用。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，黄体细胞表达多种膜受体或 P4 作用的介质。由于生殖过程需要黄体细胞活力的精确调节，因此我们有必要确定哪种受体或哪些受体在人黄体细胞中介导 P4 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，因为这种假设仅基于 nPR 表达和药理学研究。因此，我们将利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。我们提出以下三个具体目标：1）在 P4 分泌和 nPR 表达以及 P4 作用的其他潜在介质方面表征人黄体细胞体外分化和退化； 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； 3) 确定 nPR 的特异性消融和过度表达对 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，这可能会开辟新的药理学领域，旨在抑制或增强这些其他 P4 介质的作用。由于这三种候选蛋白的结构与 nPR 的结构非常不同，因此有可能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、避孕和某些类型癌症的治疗产生深远的影响。