Regulation of Preantral Follicles

腔前卵泡的调节

• 批准号: 7363484
• 负责人: ELIZABETH A MCGEE
• 金额: $ 23.48万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7363484
• 关键词: Adenoviridae; DNA replication; activins; apoptosis; biological signal transduction; developmental genetics; follicle stimulating hormone; genetic regulation; genetically modified animals; graafian follicles; granulosa cell; hormone receptor; hormone regulation /control mechanism; laboratory mouse; protein structure function; receptor binding; receptor expression; reproductive development; tissue /cell culture; transcription factor; transfection /expression vector; transforming growth factors

DESCRIPTION (provided by applicant): Folliculogenesis (the growth of an ovarian follicle from the primordial stage to ovulation) is a more prolonged event than is widely appreciated, requiring more than 220 days in humans. The vast majority of this time is spent as a preantral follicle, yet very little is known about the regulation of the growth and development of these follicles. Members of the TGFbeta growth factor family induce distinct quantifiable effects in preantral follicles in culture. Deletion of the TGFbeta family signaling molecule, Smad3 results in decreased number of preantral follicles and infertility in the mouse. Follicles deficient in Smad3 do not respond normally to FSH treatment. The overall goal of this research is to determine the regulators of early follicle development. This proposal will determine the role of Smad3 in early follicle development by achieving the following aims. Specific Aim 1- Is Smad3 essential for optimal preantral follicle growth in response to FSH? This aim will determine quantitative and qualitative changes in FSH-stimulated preantral follicle growth and development in the ovary of the Smad3 deficient mouse compared to wild-type. Specific Aim 2- Does Smad3 impact FSH stimulation of granulosa cell function? This aim will use granulosa cell culture techniques to determine the integrity of the FSH signaling pathway in the absence of Smad3 and the effects of direct modulation of Smad2 and Smad3 function on FSH signaling. Specific Aim 3 - Does manipulation of Smad3 function modulate FSH-stimulated early follicle growth? In this aim we will restore Smad3 function to Smad3 deficient preantral follicles to determine if FSH responsiveness is restored. We will also directly manipulate Smad2 and Smad3 function to determine the independent and combined roles of Smad2 and Smad3 in regulating preantral follicle development. The elucidation of the mechanisms of regulation of early follicle growth, differentiation and apoptosis has profound implications for developing new non-hormonal contraceptives and treatments for ovarian causes of infertility. Additionally, the ability to manipulate the rate of loss of follicles from the finite pool of ovarian follicles could impact the timing of menopause and ovarian aging. Increased knowledge of the determinants of healthy early follicle development will also benefit the emerging field of ovarian cryopreservation and in vitro follicle development.

描述（由申请人提供）：卵泡发生（从原始阶段到排卵的卵巢卵泡的生长）比广泛欣赏的事件更长，需要在人类中超过220天。这段时间的绝大多数是一种卵泡的毛囊，但对这些卵泡的生长和发育的调节知之甚少。 TGFBETA生长因子家族的成员在培养物中会引起在培养卵泡中的明显可量化作用。 TGFBETA家族信号分子的删除，SMAD3导致小鼠毛囊的数量减少和不育。缺乏SMAD3的卵泡对FSH治疗不正常反应。这项研究的总体目标是确定早期卵泡发育的调节剂。该提案将通过实现以下目标来确定SMAD3在早期卵泡发育中的作用。特定的目标1- SMAD3对于响应FSH而言，对于最佳的酸卵泡生长至关重要吗？与野生型相比，此目标将确定FSH刺激的卵泡卵泡卵泡的生长和发育的定量和定性变化。特定的目标2- smad3会影响颗粒细胞功能的FSH刺激吗？该目标将使用颗粒细胞培养技术在没有SMAD3的情况下确定FSH信号通路的完整性，以及SMAD2和SMAD3功能直接调制对FSH信号传导的影响。特定目标3-对SMAD3功能的操作是否调节FSH刺激的早期卵泡生长？在此目标中，我们将将SMAD3功能恢复为SMAD3缺乏尿布卵泡，以确定是否恢复FSH响应能力。我们还将直接操纵SMAD2和SMAD3函数，以确定SMAD2和SMAD3在调节尿液卵泡发育中的独立和组合作用。 阐明早期卵泡生长，分化和凋亡的调节机制对开发新的非激素避孕药和治疗卵巢不育原因具有深远的影响。此外，操纵卵巢卵泡有限池卵泡损失率的能力可能会影响更年期和卵巢老化的时间。对健康早期卵泡发育的决定因素的知识增加也将使卵巢冷冻保存和体外卵泡发育的新兴领域有益。