FAS ANTIGEN AND OVARIAN CELL APOPTOSIS

FAS抗原与卵巢细胞凋亡

• 批准号: 2668588
• 负责人: SUSAN MARY QUIRK
• 金额: $ 10.89万
• 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/2668588
• 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 调控卵巢细胞的程序性死亡。Fas抗原是一种 触发细胞凋亡的跨膜受体(一种程序化细胞 死亡)。该项目将确定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配体在不同类型细胞中的表达 用原位杂交法对循环小鼠卵巢进行检测。量化变化 Fas抗原在诱导卵泡发育过程中的表达水平 逆转录聚合酶链式反应和流式细胞术检测黄体发育和退化。 (B)研究不同药物对体外Fas抗原表达的调节作用 卵泡和黄体细胞分化和退化的介体 (促性腺激素、生长因子和细胞因子)。这些药物对人体健康的影响 细胞对Fas抗原介导的细胞凋亡的敏感性将被确定。 Fas抗原在人颗粒/黄体细胞中表达， 抗Fas抗原单抗与受体的结合 (Fas单抗)诱导细胞凋亡。这些结果为以下研究提供了依据 Fas抗原在触发卵泡中的潜在作用研究 闭锁和/或黄体溶解。 卵泡被刺激离开静止期并开始 以一种未知的机制生长，从出生前就开始并持续下去 在一生中。卵泡对生长途径的承诺是 不可逆，并导致两个可能的终点之一：排卵或 退化。卵巢中存在的卵泡中，只有不到1%是 注定要排卵，而绝大多数人在 在发展过程中的一些状态。排卵后卵泡 细胞分化形成黄体。黄体有一个 有限的寿命在退化中终结。启蒙因素 卵泡闭锁和黄体溶解知之甚少。最近的证据 细胞凋亡导致的卵泡闭锁和黄体溶解提供了新的 深入了解这些流程。 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 不孕不育和生育能力的提高。了解以下路径 诱导卵巢细胞凋亡可能导致新的 卵巢癌和其他癌症的治疗方法。此外，卵巢提供了 一种优秀而独特的细胞凋亡研究模型 在生命的整个过程中，单个器官内都会发生细胞凋亡的循环。这 实验室拥有卵巢生理和技术方面的设施和专业知识 进行这些研究的分子生物学。