Regulation of Preantral Follicles

腔前卵泡的调节

• 批准号: 7038283
• 负责人: ELIZABETH A MCGEE
• 金额: $ 3.24万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038283
• 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（卵泡从原始阶段到排卵的生长）是一个比人们普遍认为的更长的事件，在人类中需要超过 220 天。绝大多数时间都花在腔前卵泡上，但人们对这些卵泡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的窦前卵泡中诱导独特的可量化效应。删除 TGFbeta 家族信号分子 Smad3 会导致小鼠窦前卵泡数量减少和不育。缺乏 Smad3 的卵泡对 FSH 治疗没有正常反应。这项研究的总体目标是确定早期卵泡发育的调节因子。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。具体目标 1 - Smad3 对于响应 FSH 的最佳腔前卵泡生长至关重要吗？这一目标将确定与野生型相比，Smad3 缺陷小鼠卵巢中 FSH 刺激的腔前卵泡生长和发育的定量和定性变化。具体目标 2-Smad3 是否会影响 FSH 对颗粒细胞功能的刺激？该目标将使用颗粒细胞培养技术来确定在缺少 Smad3 的情况下 FSH 信号通路的完整性以及直接调节 Smad2 和 Smad3 功能对 FSH 信号传导的影响。具体目标 3 - Smad3 功能的操纵是否会调节 FSH 刺激的早期卵泡生长？为此，我们将恢复 Smad3 缺陷的窦前卵泡的 Smad3 功能，以确定 FSH 反应性是否恢复。我们还将直接操纵Smad2和Smad3功能，以确定Smad2和Smad3在调节窦前卵泡发育中的独立和联合作用。 阐明早期卵泡生长、分化和凋亡的调节机制对于开发新的非激素避孕药和治疗卵巢原因不孕症具有深远的意义。此外，控制有限卵泡池中卵泡丢失率的能力可能会影响绝经和卵巢衰老的时间。对健康早期卵泡发育决定因素的更多了解也将有利于卵巢冷冻保存和体外卵泡发育的新兴领域。