Activation of dormant ovarian follicles

激活休眠的卵泡

• 批准号: 7849497
• 负责人: AARON JW HSUEH
• 金额: $ 20.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849497
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Aging; Antral; Cell Cycle Regulation; Data; Derivation procedure; Development; Embryo Transfer; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exposure to; Fertility; Fertilization; Fertilization in Vitro; Genes; Growth; Hormonal; In Vitro; Infertility; Kidney; Life; Menopause; Modeling; Mus; Mutant Strains Mice; Neonatal; Newborn Animals; Oocytes; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Pregnancy; Premature Ovarian Failure; Primordial Follicle; Procedures; Protocols documentation; Public Health; Recruitment Activity; Reporting; Rest; Retrieval; Rodent; Safety; Signal Pathway; Staging; Transplantation; Treatment Protocols; Tumor Suppressor Proteins; Woman; base; capsule; efficacy testing; exhaustion; in vitro Model; in vivo; inhibitor/antagonist; intraovarian; neonatal exposure; novel strategies; offspring; premature; public health relevance; reproductive; safety testing; tensin

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.

描述（由申请人提供）：哺乳动物卵巢由卵泡作为基本功能单位组成。卵巢卵泡的总数在生命的早期就决定了，这个池子的耗尽会导致生殖衰老。在卵泡的初始募集过程中，未知的卵巢内机制刺激或释放少量原始卵泡以启动生长，而其余的卵泡则保持数月或数年的静止状态。一旦进入生长池，卵巢卵泡继续生长，直到早期心房阶段，损失最小。对于那些没有被招募的卵泡，默认的途径是保持休眠状态。尽管休眠卵泡初始募集的确切机制尚不清楚，但最近对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）基因促进了新生动物所有原始卵泡的生长，导致整个卵泡池的衰竭和随后的卵巢早衰。PTEN基因编码一种磷酸酶，该磷酸酶负调控磷脂酰肌醇3-激酶（PI3K）和PKB/Akt信号通路，这对细胞周期调控很重要。卵母细胞中PTEN的缺失刺激PI3K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。短暂暴露于PTEN抑制剂的新生儿卵巢在移植到经fsh处理的成人受体肾包膜后，卵泡生长明显增加。我们建议完善目前的体外PTEN抑制剂治疗模型，然后进行体内卵巢移植，以证明这种卵泡激活模型对排卵前卵母细胞的衍生和健康后代的有效性和安全性。虽然卵巢早衰患者和围绝经期妇女的生育能力受到损害，但她们的卵巢仍含有少量的原始卵泡。目前，在体外短暂和卵巢特异性暴露于PTEN抑制剂，然后进行体内移植，可以为不孕症治疗提供一种恢复功能的排卵前卵母细胞的新方法。公共卫生相关性：目前的应用涉及使用酶抑制剂来启动休眠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，目前的治疗方案可能有利于患者卵巢早衰和不孕妇女围绝经期过渡。