Regulation of Oocyte Viability by Granulosa Cell Contact

描述（由申请人提供）：一旦原始卵泡数量耗尽，就会发生更年期。此外，原始卵泡的快速消耗与年龄相关的生育能力下降和卵巢早衰有关。据估计，约70%的卵泡由于卵母细胞死亡而丢失。除此之外，对这些小卵泡维持的机制知之甚少。深入了解影响原始卵泡的生存机制可能来自于了解这些卵泡是如何形成的。 在胚胎发育过程中，原始生殖细胞（PGCs）迁移到发育中的哺乳动物卵巢，增殖，然后进入减数分裂前期。在这个阶段，许多PGCs通过称为凋亡的特定途径死亡。然而，一些PGCs与体细胞（假定颗粒细胞）建立接触，形成原始卵泡。这些PGCs，现在被称为卵母细胞，似乎受到保护，免于凋亡。这一过程发生在所有哺乳动物物种，包括人类。虽然几十年来人们已经知道细胞接触似乎可以保护卵母细胞免于死亡，但细胞接触促进卵母细胞存活的机制完全未知。 已知颗粒细胞-卵母细胞相互作用部分由粘附蛋白E-和N-钙粘蛋白介导。基于我们以前对颗粒细胞凋亡的研究，我们提出E-和/或N-钙粘蛋白介导的细胞接触刺激卵母细胞内的磷脂酰肌醇3激酶（PI 3 K）活性。进一步提出，PI 3 K最终起到维持卵母细胞活力的作用。 了解颗粒细胞如何与卵母细胞相互作用，以保持卵母细胞的活力，可以提供重要的见解不孕症的各个方面和控制进入更年期的机制。因此，我们将确定：1）颗粒细胞接触对卵母细胞在体外经历细胞凋亡的速率的影响; 2）E-和/或N-钙粘蛋白介导的细胞接触是否调节卵母细胞活力;和3）E-和/或N-钙粘蛋白介导的细胞接触是否刺激PI 3 K活性，从而维持卵母细胞活力。

DESCRIPTION (provided by applicant): Menopause occurs once the number of primordial follicles is depleted. Moreover, a rapid depletion of primordial follicles is associated with the age-related decline in fertility and premature ovarian failure. It has been estimated that about 70% of these follicles are lost because of oocyte death. Other than this, extremely little is known about the mechanism by which these small follicles are maintained. Insight into the survival mechanisms that influence primordial follicles could come from understanding how these follicles are formed. During embryonic development, primordial germ cells (PGCs) migrate into the developing mammalian ovary, proliferate and then enter meiotic prophase. At this stage, many of the PGCs die via a specific pathway known as apoptosis. However, some PGCs establish contact with somatic cells (presumptive granulosa cells) to form primordial follicles. These PGCs, now referred to as oocytes, appear to be protected from undergoing apoptosis. This process occurs in all mammalian species including humans. While it has been known for decades that cell contact seems to protect oocytes from dying, the mechanism through which cell contact promotes oocyte survival is completely unknown. It is known that granulosa cell-oocyte interaction is mediated, in part, by the adhesion proteins, E- and N-cadherin. Based on our previous studies of granulosa cell apoptosis, we propose that E- and/or N-cadherin mediated cell contact stimulates phosphatidylinositol 3 kinase (PI3K) activity within the oocyte. It is further proposed that PI3K ultimately acts to maintain the viability of the oocyte. Understanding how granulosa cells interact with oocytes to preserve oocyte viability could provide important insights into various aspects of infertility and the mechanisms that control entry into menopause. Therefore, we will determine: 1) the effect of granulosa cell contact on the rate at which oocytes undergo apoptosis in vitro; 2) whether E- and/or N-cadherin mediated cell contact regulates oocyte viability; and 3) whether E- and/or N-cadherin mediated cell contact stimulates PI3K activity and thereby maintains oocyte viability.