FAS AND BC1-2 AND GRANULOSA CELL APOPTOSIS

候选人 候选人接受过妇产科培训， 已完成生殖内分泌学的亚专业奖学金。 他 一直积极从事人类颗粒细胞的基础研究 生理学超过4年，并有经验，与一些 本提案中使用的技术。 他出版了五本第一作者的著作。 论文，并已提交另一个（附录）。 研究计划。 在胚胎和胎儿发育过程中， 人类卵巢中的卵母细胞增加，直到妊娠中期，之后， 在绝经期前会逐渐下降 卵母细胞没有被 颗粒细胞几乎在卵巢发育过程中发生闭锁， 卵泡在发育的每个阶段也会发生闭锁， 原始到第三窦期。 绝大多数卵母细胞是 由于闭锁而消失;只有少数成熟到排卵。 在非人 模型，窦卵泡闭锁与颗粒细胞 凋亡或程序性细胞死亡。 细胞凋亡的激活可以是 受细胞外（细胞因子、生长因子））和 细胞内机制 调节非细胞因子的细胞外因子 人颗粒细胞凋亡已有报道。 拟议的研究 试图确定人类颗粒细胞信号的细胞内通路， 细胞凋亡，以及来源和身份， 细胞外效应物通过这些细胞因子激活凋亡信号， 途径。 对颗粒细胞过程的认识 细胞凋亡可能有助于设计新的治疗方法，以延缓细胞凋亡的损失。 伴随正常衰老和恶性肿瘤治疗的卵母细胞。 本提案的具体目的是调查 细胞内凋亡调节分子Fas/APO-1和Bcl-2在 人卵巢，以及细胞因子干扰素-γ（IFN-γ）的作用， γ）和肿瘤坏死因子-α（TNF-α）在传递 凋亡信号 这些研究也可能有助于确定 凋亡信号来源于卵巢实质细胞或 白细胞 据推测，在人类颗粒细胞中， Fas的激活促进细胞凋亡，而Bcl-2的过度表达 其拮抗剂Bax可阻止细胞凋亡。 进一步假设， IFN-γ诱导Fas表达，而TNF-α可能诱导凋亡 通过自己的受体。 环境 美国密歇根大学生殖内分泌中心 加州，旧金山弗朗西斯科由NIH资助#HD 11979支持。 列入 该中心是形态学、分子生物学和放射免疫分析核心， 研究人员可利用的设施。 主 申办者的实验室和这些核心包含所有必要的设备 对于提出的研究。

Candidate. The candidate has been trained in obstetrics and gynecology and has completed a subspecialty fellowship in Reproductive Endocrinology. He has been actively engaged in basic research on human granulosa cell physiology for over 4 years and has experience with a number of the techniques to be used in this proposal. He has published five first-author papers, and another has been submitted (Appendix). Research plan. During embryonic and fetal development, the number of oocytes in the human ovary increases until mid-gestation, after which it steadily declines until the menopause. Oocytes which are not surrounded by granulosa cells nearly i ovarian development undergo atresia, while follicles also undergo atresia at every stage of development from the primordial to the tertiary antral stage. The vast majority of oocytes are lost through atresia; only a minority mature to ovulation. In non-human models, atresia of antral follicles has been associated with granulosa cell apoptosis, or programmed cell death. Activation of apoptosis can be regulated by both extracellular (cytokine, growth facto) and intracellular mechanisms. The extracellular factors which regulate non- human granulosa cell apoptosis are being reported. The proposed studies seek to identify the intracellular pathways that signal the human granulosa cell to undergo apoptosis, as well as the source and identity of th extracellular effectors that activate the apoptotic signal through these pathways. A better understanding of the process of granulosa cell apoptosis may aid in the design of new therapies to retard the loss of oocytes that accompanies both normal aging and therapies for malignancy. The specific aims of this proposal are to investigate the roles of the intracellular apoptosis-regulating molecules Fas/APO-1 and Bcl-2 in the human ovary, as well as the roles of the cytokines interferon-gamma (IFN- gamma) and tumor necrosis factor-alpha (TNF-alpha) in transmitting the apoptotic signal. These studies may also help to determine whether the apoptotic signal originates within ovarian parenchymal cells or from leukocytes. It is hypothesized that in human granulosa cells, expression and activation of Fas promotes apoptosis, while Bcl-2 expression in excess of its antagonist Bax prevents apoptosis. It is further hypothesized that IFN-gamma induces Fas expression, while TNF-alpha may induce apoptosis through its own receptor. Environment. The Reproductive Endocrinology Center at the university of California, San Francisco is supported by NIH Grant #HD11979. Included in the Center are Morphology, Molecular Biology, and Radioimmunoassay Cores, the facilities of which are available to the investigator. The Primary Sponsor's laboratory and these Cores contain all of the necessary equipment for the studies proposed.