Activation of dormant ovarian follicles

激活休眠的卵泡

• 批准号: 7640438
• 负责人: AARON JW HSUEH
• 金额: $ 24.03万
• 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/7640438
• 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。卵泡总数在生命早期就已确定，卵泡池的耗尽会导致生殖衰老。在卵泡最初募集过程中，未知的卵巢内机制刺激或释放少量原始卵泡以开始生长，而其余卵泡则保持静止数月或数年。一旦进入生长池，卵泡就会继续生长，直到早期窦期，损失最小。对于那些未募集的卵泡，默认途径是保持休眠状态。尽管最初招募休眠卵泡的确切机制尚不清楚，但最近使用突变小鼠的研究表明，卵母细胞特异性删除 PTEN（具有 TENsin 同源性的肿瘤抑制磷酸酶）基因促进了新生动物中所有原始卵泡的生长，导致整个卵泡池耗尽并随后导致卵巢早衰。 PTEN 基因编码一种磷酸酶，可负向调节磷脂酰肌醇 3-激酶 (PI3K) 和对细胞周期调节很重要的 PKB/Akt 信号通路。卵母细胞中 PTEN 的缺失会刺激 PI3K 活性，并激活所有休眠的原始卵泡。利用 PTEN 抑制剂的优势，我们获得了显示新生小鼠原始卵泡激活的初步数据。体外短暂暴露于 PTEN 抑制剂的新生儿卵巢在移植到接受 FSH 治疗的成年受者的肾被膜后显示卵泡生长显着增加。我们建议完善现有的体外 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于产生排卵前卵母细胞和健康后代的有效性和安全性。尽管卵巢早衰患者和围绝经期妇女的生育能力受到损害，但她们的卵巢仍含有少量原始卵泡。目前在体外短暂且卵巢特异性地暴露于 PTEN 抑制剂，然后进行体内移植，可以提供一种获取功能性排卵前卵母细胞以用于不孕症治疗的新方法。公共健康相关性：本申请涉及使用酶抑制剂来启动休眠卵巢原始卵泡的生长，以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。