ROLE OF THE FAS ANTIGEN IN OVARIAN CELL APOPTOSIS

FAS 抗原在卵巢细胞凋亡中的作用

• 批准号: 6520951
• 负责人: SUSAN MARY QUIRK
• 金额: $ 25.04万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520951
• 关键词: CD95 molecule; apoptosis; aromatase; cell cycle proteins; cell proliferation; corpus luteum; cow; cyclins; developmental genetics; estradiol; flow cytometry; gene expression; gene induction /repression; graafian follicles; granulosa cell; growth factor; immunocytochemistry; luteinizing hormone; molecular dynamics; ovary disorder; polymerase chain reaction; progesterone receptors; radioimmunoassay; tissue /cell culture; western blottings

DESCRIPTION: (Scanned from the applicant's abstract) The proposed experiments will test the hypothesis that alterations in the cell cycle during ovarian follicle development modulate the susceptibility of follicle cells to undergo apoptosis. These changes affect critical stages of follicle development including (1) selection of the dominant follicle for development to the ovulatory stage and (2) terminal differentiation of granulosa cells after the preovulatory luteinizing hormone (LH) surge. Our previous work demonstrated the presence of a functional Fas antigen (Fas) pathway in the ovarian follicle. Fas is a cell surface receptor that induces apoptosis in sensitive cells when bound by Fas ligand (FasL). Granulosa and theca cells can express both Fas and FasL and expression varies with follicle development during the estrous cycle. The Fas pathway is highly regulated in ovarian cells and is modulated by growth factors and cytokines. Bovine granulosa cells from preovulatory follicles that are exposed to an LH surge in vivo become resistant to FasL-induced and serum withdrawal-induced apoptosis. Specific aim I is to determine whether resistance to apoptosis is mediated by: A. Withdrawal from the cell cycle induced by cell cycle regulatory proteins and/or B. Induction of the progesterone receptor and subsequent progesterone receptor-mediated effects on the cell cycle. Specific aim II is to determine the mechanism for inhibition of FasL-induced apoptosis of bovine granulosa cells by growth factors. In specific aim III the effect of modulating the cell cycle on susceptibility of granulosa cells to apoptosis will be determined. Specific aim IV is to test the hypothesis that estradiol inhibits FasL-induced apoptosis of granulosa cells by modulating the cell cycle. Relationships among aromatase expression, cyclin D2 expression, granulosa cell proliferation and escape from apoptosis during selection of the dominant follicle will be determined. An understanding of follicle atresia is essential to allow development of improved methods of fertility control, treatment of infertility and enhancement of fertility. Understanding pathways that promote or prevent susceptibility of ovarian cells to apoptosis may lead to development of novel therapies for ovarian and other cancers.

描述：(摘自申请者的摘要)提议的实验 将检验这样一种假设，即卵巢细胞周期的变化 卵泡发育调节卵泡细胞的易感性 细胞凋亡。这些变化影响卵泡发育的关键阶段。 包括(1)选择优势卵泡以发育到 排卵期和(2)卵巢颗粒细胞终末分化。 排卵前促黄体生成素(LH)激增。我们以前的工作演示了 卵泡中存在功能性Fas抗原(Fas)途径。FAS 是一种细胞表面受体，当结合时可诱导敏感细胞的凋亡 Fas配体(FasL)。颗粒细胞和膜细胞同时表达Fas和FasL 在发情周期中，随着卵泡发育的不同，其表达也会发生变化。这个 Fas途径在卵巢细胞中高度调控，并受生长调节 因子和细胞因子。来自排卵前卵泡的牛颗粒细胞 暴露于体内的黄体生成素激增，对FasL诱导的血清和 戒断诱导的细胞凋亡。我的具体目标是确定耐药性 通过：A.由细胞诱导的细胞周期的退出 周期调节蛋白和/或B.孕激素受体和 随后孕激素受体对细胞周期的影响。特定的 目的II确定抑制FasL诱导的细胞凋亡的机制 生长因子对牛颗粒细胞的影响。在特定目标三中的效果 调控细胞周期对颗粒细胞凋亡易感性的影响 将会被确定。具体目标四是检验雌二醇的假设 通过调控细胞抑制FasL诱导的颗粒细胞凋亡 周而复始。芳香酶表达与细胞周期蛋白D2表达的关系 颗粒细胞的增殖和逃避细胞凋亡的选择 将确定优势卵泡。对卵泡闭锁的认识是 对于开发改进的生育控制方法是至关重要的， 治疗不孕不育，提高生育力。了解途径 促进或阻止卵巢细胞对凋亡的易感性可能会导致 为卵巢癌和其他癌症开发新的治疗方法。