Activation of dormant ovarian follicles

描述(申请人提供)：哺乳动物卵巢由作为基本功能单位的卵泡组成。卵巢卵泡的总数是在生命早期就确定的，这个池的耗尽会导致生殖衰老。在卵泡的初始募集期间，未知的卵巢内机制刺激或释放少量原始卵泡以启动生长，而其余的卵泡保持静止数月或数年。一旦进入生长池，卵泡就会继续生长，直到有腔的早期，损失最小。对于那些未被招募的卵泡，默认途径是保持休眠。虽然休眠卵泡最初募集的确切机制尚不清楚，但最近使用突变小鼠的研究表明，卵母细胞特异性的PTEN(肿瘤抑制同源磷酸酶)基因的缺失促进了新生动物所有原始卵泡的生长，导致整个卵泡池的耗尽和随后的卵巢早衰。PTEN基因编码一种磷酸酶，负调控磷脂酰肌醇3-激酶(PI3K)和PKB/Akt信号通路，该信号通路对细胞周期调控至关重要。卵母细胞中PTEN的缺失刺激了PI3K的活性，并允许所有休眠的原始卵泡激活。利用PTEN抑制剂的可用性，我们获得了显示新生小鼠原始卵泡激活的初步数据。在体外短暂暴露于PTEN抑制剂的新生儿卵巢，在移植到FSH治疗的成年受者的肾被膜后，卵泡生长显著增加。我们建议改进目前的PTEN抑制剂体外治疗模型，然后进行体内卵巢移植，以证明这种卵泡激活模型在获得排卵前卵母细胞和健康后代方面的有效性和安全性。尽管卵巢早衰患者和围绝经期妇女的生育力受到影响，但他们的卵巢中仍然含有少量的原始卵泡。PTEN抑制剂在体外的瞬时和卵巢特异性暴露，以及随后的体内移植，可能为获取功能性排卵前卵母细胞用于不孕症治疗提供一种新的途径。公共卫生相关性：本申请涉及使用一种酶抑制剂来启动休眠的卵巢原始卵泡的生长，以便随后成熟为排卵前卵泡。一旦优化，目前的治疗方案可以使卵巢早衰患者和围绝经期过渡期间的不孕妇女受益。

DESCRIPTION (provided by applicant): Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive aging. During initial recruitment of follicles, unknown intraovarian mechanisms stimulate or release a small number of primordial follicles to initiate growth, whereas the rest of the follicles remain quiescent for months or years. Once entering the growing pool, ovarian follicles continue to grow until the early antral stage with minimal loss. For those follicles not recruited, the default pathway is to remain dormant. Although the exact mechanisms underlying the initial recruitment of dormant follicles is unknown, recent studies using mutant mice indicated that oocyte-specific deletion of the PTEN (Tumor-suppressor phosphatase with TENsin homology) gene promoted the growth of all primordial follicles in neonatal animals, leading to the exhaustion of the entire follicle pool and subsequent premature ovarian failure. The PTEN gene encodes a phosphatase enzyme that negatively regulates the phosphatidylinositol 3-kinase (PI3K) and PKB/Akt signalling pathway important for cell cycle regulation. Deletion of PTEN in the oocyte stimulates PI3K activity and allows the activation of all dormant primordial follicles. Taking advantage of the availability of PTEN inhibitors, we obtained preliminary data showing the activation of primordial follicles in neonatal mice. Neonatal ovaries exposed transiently to PTEN inhibitors in vitro showed marked increases in follicle growth after transplantation into the kidney capsule of FSH-treated adult recipients. We propose to refine the present model of in vitro PTEN inhibitor treatment, followed by in vivo ovarian transplantation, to demonstrate the efficacy and safety of this follicle activation model for the derivation of preovulatory oocytes and healthy offspring. Although fertility is compromised in patients with premature ovarian failure and peri-menopausal women, their ovaries still contain small number of primordial follicles. The present transient and ovary-specific exposure to PTEN inhibitors in vitro, followed by in vivo transplantation, could provide a new approach to retrieve functional preovulatory oocytes for infertility treatment. PUBLIC HEALTH RELEVANCE: The present application deals with the use of an enzyme inhibitor to initiate the growth of dormant ovarian primordial follicles for subsequent maturation into preovulatory follicles. Once optimized, the present treatment protocol could benefit patients with premature ovarian failure and infertile women during peri-menopausal transition.