FAS ANTIGEN AND OVARIAN CELL APOPTOSIS

FAS抗原与卵巢细胞凋亡

• 批准号: 2883138
• 负责人: SUSAN MARY QUIRK
• 金额: $ 11.33万
• 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 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2883138
• 关键词: CD95 molecule; apoptosis; cell differentiation; cell mediated cytotoxicity; cell type; corpus luteum; cytotoxicity; developmental genetics; epidermal growth factor; flow cytometry; gene expression; gene induction /repression; granulosa cell; in situ hybridization; interferon gamma; laboratory mouse; ligands; luteinizing hormone; messenger RNA; monoclonal antibody; ovary disorder; polymerase chain reaction; tissue /cell culture; tumor necrosis factor alpha

The overall goal is to identify triggering events and molecular mechanisms regulating programmed cell death of ovarian cells. The Fas antigen is a transmembrane receptor which triggers apoptosis (a form of programmed cell death). The project will define the role of the Fas antigen in ovarian follicular atresia and luteolysis. The specific aims are: (A) Determine Fas antigen and Fas ligand mRNA expression in specific cell types in the ovary of the cycling mouse using in situ hybridization. Quantify changes in levels of expression of Fas antigen during induction of follicular and corpus luteum development and regression using RT-PCR and flow cytometry. (B) Study modulation of expression of Fas antigen in vitro by various mediators of follicular and luteal cell differentiation and degeneration (gonadotropins, growth factors and cytokines). Effects of these agents on sensitivity of cells to Fas antigen-mediated apoptosis will be determined. The Fas antigen is expressed in human granulosa/luteal cells and engagement of the receptor with an anti-Fas antigen monoclonal antibody (Fas mAB) induces apoptosis. These results provide a rationale for studying a potential role of the Fas antigen in triggering follicular atresia and/or luteolysis. Ovarian follicles are stimulated to leave the resting stage and begin to grow by an undefined mechanism beginning before birth and continuing throughout life. Commitment of a follicle to the growth pathway is irreversible and results in one of two possible endpoints: ovulation or degeneration. Less than 1% of the follicles present in the ovary are destined to ovulate while the vast majority become atretic (degenerate) at some state in the developmental process. Following ovulation follicular cells differentiate and form the corpus luteum. The corpus luteum has a limited life-span terminating in degeneration. The factors initiating follicular atresia and luteolysis are poorly understood. Recent evidence that follicular atresia and luteolysis occur by apoptosis has provided new insight into these processes. An understanding of follicular atresia and luteolysis is essential to allow development of improved methods of fertility control, treatment of infertility and enhancement of fertility. Understanding pathways that induce apoptosis in ovarian cells may lead to development of novel therapies for ovarian and other cancers. Furthermore, the ovary provides an excellent and unique model for the study of apoptosis since continual cycles of apoptosis occur within a single organ throughout life. This laboratory has the facilities and expertise in ovarian physiology and molecular biology to undertake these studies.

总体目标是确定触发事件和分子机制 调节卵巢细胞的程序性细胞死亡。 Fas 抗原是 触发细胞凋亡（程序性细胞的一种形式）的跨膜受体 死亡）。 该项目将明确 Fas 抗原在卵巢中的作用 卵泡闭锁和黄体溶解。 具体目标是： (A) 确定 Fas 抗原和 Fas 配体 mRNA 在特定细胞类型中的表达 使用原位杂交观察循环小鼠的卵巢。 量化变化 卵泡诱导过程中 Fas 抗原的表达水平 使用 RT-PCR 和流式细胞术观察黄体发育和退化。 (B) 研究各种因素对 Fas 抗原表达的体外调节 卵泡和黄体细胞分化和退化的介质 （促性腺激素、生长因子和细胞因子）。 这些药剂的影响 将确定细胞对Fas抗原介导的细胞凋亡的敏感性。 Fas 抗原在人颗粒/黄体细胞中表达，并且 受体与抗 Fas 抗原单克隆抗体的结合 (Fas mAB) 诱导细胞凋亡。 这些结果提供了理由 研究 Fas 抗原在触发卵泡中的潜在作用 闭锁和/或黄体溶解。 卵巢卵泡受到刺激离开静止阶段并开始 通过一种未定义的机制从出生前开始并持续生长 一生。 卵泡对生长途径的承诺是 不可逆并导致两个可能终点之一：排卵或 退化。 卵巢中只有不到 1% 的卵泡是 注定要排卵，而绝大多数则在以下时间变得闭锁（退化） 发育过程中的某种状态。 排卵后卵泡 细胞分化并形成黄体。 黄体有一个 寿命有限，最终退化。 引发因素 人们对卵泡闭锁和黄体溶解知之甚少。 最近的证据 细胞凋亡导致卵泡闭锁和黄体溶解提供了新的 深入了解这些过程。 了解卵泡闭锁和黄体溶解对于 允许开发改进的生育控制方法、治疗 不孕不育和提高生育能力。 了解途径 诱导卵巢细胞凋亡可能导致新的开发 卵巢癌和其他癌症的治疗。 此外，卵巢还提供 自连续不断的研究以来，它成为细胞凋亡研究的一个优秀而独特的模型 细胞凋亡周期在整个生命过程中发生在单个器官内。 这 实验室拥有卵巢生理学方面的设施和专业知识 分子生物学承担这些研究。