PRIMORDIAL FOLLICLE ENDOWMENT AND REPRODUCTIVE AGING

雌性哺乳动物出生时就有不能补充的卵母细胞储备 随着时间的推移，这些资源逐渐枯竭。这样做的长期目标是 工作是确定原始捐赠的规模是否发生变化 卵母细胞的数量会影响生育寿命的长短 生育年限内的生殖能力。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。胚胎的有丝分裂 细胞产生了大量的卵原细胞，但这个种群 立即被大量的细胞凋亡波所减少 胚胎生命的最后几天。此应用程序的具体目标是 验证bcl2在卵原细胞中过表达将 减少胚胎期生殖细胞的损失，从而产生过量 新生小鼠原始卵泡的数量。转基因小鼠将成为 产生携带人类bcl2基因的基因，由c-kit控制 推动者。“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。表达C-KIT 大量的生殖细胞就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 在含有非常高浓度的bcl2的时候 最有可能发生细胞凋亡。这可能会阻止细胞凋亡， 从而提高生殖细胞的存活率并导致过度的 原始卵泡的天赋。转基因小鼠的卵巢将 出生后不久通过组织形态计量学进行评估以确定 如果它们含有超过正常数量的卵母细胞。这个实验 在此应用程序中提出的可能会生成 转基因动物模型对广泛研究将是无价的 关于原始卵泡储备的问题。

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.