Activation of dormant ovarian follicles

描述（由申请方提供）：哺乳动物卵巢由作为基本功能单位的卵泡组成。卵巢卵泡的总数在生命早期就决定了，这个池的消耗导致生殖老化。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，而其余卵泡保持静止数月或数年。一旦进入生长池，卵泡继续生长，直到早期窦期，损失最小。对于那些没有募集的卵泡，默认的途径是保持休眠。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，卵母细胞特异性缺失PTEN（具有TENSin同源性的肿瘤抑制磷酸酶）基因促进新生动物中所有原始卵泡的生长，导致整个卵泡池耗尽，随后出现卵巢早衰。PTEN基因编码磷酸酶，其负调节磷脂酰肌醇3-激酶（PI 3 K）和对细胞周期调节重要的PKB/Akt信号传导途径。卵母细胞中PTEN的缺失刺激PI 3 K活性，并允许激活所有休眠的原始卵泡。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。在体外将新生儿卵巢短暂暴露于PTEN抑制剂后，移植到FSH治疗的成年受者的肾包膜中后，卵泡生长显着增加。我们建议完善本模型的体外PTEN抑制剂治疗，然后在体内卵巢移植，以证明这种卵泡激活模型的排卵前卵母细胞和健康后代的衍生的有效性和安全性。虽然卵巢早衰患者和围绝经期妇女的生育能力受到影响，但他们的卵巢仍然含有少量的原始卵泡。目前暂时和卵巢特异性暴露于PTEN抑制剂在体外，随后在体内移植，可以提供一种新的方法来检索功能排卵前卵母细胞不孕症的治疗。公共卫生相关性：本申请涉及酶抑制剂用于启动休眠的卵巢原始卵泡生长以随后成熟为排卵前卵泡的用途。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.