PRIMORDIAL FOLLICLE ENDOWMENT AND REPRODUCTIVE AGING

原始卵泡禀赋与生殖衰老

• 批准号: 2330224
• 负责人: ANNE N HIRSHFIELD
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2330224
• 关键词: aging; apoptosis; cell cycle; early embryonic stage; egg /ovum; fertility; gene expression; gene targeting; genetic promoter element; genetically modified animals; graafian follicles; histology; laboratory mouse; oncogenes; ovary disorder; protooncogene

Female mammals are born with a non-replenishable stockpile of oocytes that is gradually depleted over time. The long-range objective of this work is to determine whether a change in size of the original endowment of oocytes will affect the duration of the fertile lifespan and reproductive competence during the fertile years. The original number of oocytes is determined by two events that occur during the embryonic period: germ cell proliferation and germ cell death. Mitosis of germ cells generates a vast population of oogonia but this population is immediately reduced by a massive wave of apoptosis that occurs during the final days of embryonic life. The specific aim of this application is to test the hypothesis that overexpression of BCL-2 in the oogonia will reduce germ cell loss during the embryonic period, producing a surfeit of primordial follicles in the neonatal mouse. Transgenic mice will be produced that carry the human BCL-2 gene, controlled by the c-kit promoter. Overexpression of the "survival gene" BCL-2 has been shown to prevent apoptotic cell death in other tissues. c-kit is expressed abundantly by the germ cells just prior to their massive wave of degeneration. Thus, the germ cells of these transgenic mice should contain very high concentrations of BCL-2 at the very time when they would be most likely to undergo apoptosis. This may prevent apoptosis, leading to enhanced survival of germ cells and resulting in an over- endowment of primordial follicles. Ovaries of the transgenic mice will be evaluated by histological morphometry shortly after birth to determine if they contain a greater-than-normal number of oocytes. The experiment proposed in this application has the potential for generating a transgenic animal model that will be invaluable for studying a wide range of questions concerning the primordial follicle stockpile.

雌性哺乳动物生来就有不可补充的卵母细胞储备 随着时间的推移逐渐耗尽。本次活动的长远目标 工作是确定原捐赠规模是否发生变化 卵母细胞的数量会影响受孕寿命的持续时间 生育期内的生殖能力。原来的数量 卵母细胞由胚胎期间发生的两个事件决定 时期：生殖细胞增殖和生殖细胞死亡。细菌有丝分裂 细胞产生大量的卵原细胞，但这个群体是 立即被大量的细胞凋亡减少 胚胎生命的最后几天。该应用程序的具体目的是 检验卵原细胞中 BCL-2 过度表达会影响这一假设 减少胚胎时期生殖细胞的损失，产生过剩的 新生小鼠的原始卵泡。转基因小鼠将 产生携带人类 BCL-2 基因，由 c-kit 控制 发起人。 “生存基因”BCL-2 的过度表达已被证明 防止其他组织中的细胞凋亡。 c-kit表达 大量的生殖细胞在它们的大规模浪潮之前 退化。因此，这些转基因小鼠的生殖细胞应该 含有非常高浓度的 BCL-2 最有可能发生细胞凋亡。这可能会阻止细胞凋亡， 导致生殖细胞存活率提高并导致过度 原始卵泡的禀赋。转基因小鼠的卵巢将 出生后不久通过组织学形态测定法进行评估以确定 如果它们含有超过正常数量的卵母细胞。实验 本申请中提出的方案有可能产生 转基因动物模型对于广泛的研究具有无价的价值 有关原始卵泡储备的问题。