NEURAL CONTROL OF THE PREPUBERTAL OVARY

青春期前卵巢的神经控制

• 批准号: 8357880
• 负责人: Sergio R Ojeda
• 金额: $ 4.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357880
• 关键词: Adult; Affinity; Antral; Attention; Biochemical; Brain-Derived Neurotrophic Factor; Cells; Communication; Competence; Development; Follicular cyst; Funding; Gene Targeting; Grant; Growth; Hormonal; Laboratories; Length; Mus; NGFR Protein; National Center for Research Resources; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurotrophic Tyrosine Kinase Receptor Type 1; Neurotrophic Tyrosine Kinase Receptor Type 2; Oocytes; Ovarian; Ovary; Ovulation; Pathway interactions; Physiological; Polycystic Ovary Syndrome; Primates; Principal Investigator; Production; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Regulatory Pathway; Research; Research Infrastructure; Resources; Role; Signal Transduction; Signaling Molecule; Source; Staging; System; Technology; Testing; Transgenic Mice; United States National Institutes of Health; base; cost; granulosa cell; interstitial; intraovarian; jagged1 protein; nervous system development; neuroregulation; neurotrophic factor; neurotrophin 4(5) receptor; nonhuman primate; overexpression; prepuberty; reproductive; transcriptional coactivator p75

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Much is known about the hormonal mechanisms controlling ovarian development. More recently, a major focus of attention in the field has been the identification of regulatory pathways that, operating within the ovarian microenvironment, contribute to the acquisition of ovarian reproductive competence. Within this framework, our laboratory has developed the concept that neurotrophins (NTs) and their Trk tyrosine kinase receptors, long thought to be exclusively required for the development of the nervous system are also involved in the control of ovarian function. Employing gene targeting approaches we identified trkB, the high-affinity receptor for neurotrophin- 4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF), as a signaling molecule required for early follicular growth and oocyte survival. In addition, we showed that nerve growth factor (NGF) contributes independently to the initiation of follicular growth. Other studies indicated that NGF acting via trkA receptors is also important for ovulation, but that despite this physiological role, an inappropriately sustained increase in intraovarian NGF synthesis results in functional alterations leading to the development of follicular cysts. Based on these findings, the present renewal application proposes the following Specific Aims: 1) To define the TrkB receptor isoform (full-length or truncated) required for early follicle growth and oocyte survival, and identify the cells primarily responsive to TrkB signaling. The objectives of this Aim will be achieved using Cre-loxP technology to specifically disrupt the expression of full-length and truncated TrkB isoforms in either oocytes or granulosa cells. 2) To test the hypothesis that NTs signaling via TrkB receptors promote early follicular growth by supporting an oocyte-to granulosa cell Jagged 1-Notch2 communication pathway. This aim will be achieved with the combined use of cell-specific trkB KOs and cellular/biochemical approaches to define the relationship that exists between TrkB signaling and the Notch2 pathway. 3) To test the hypotheses that while NGF- dependent trkA signaling is required for the normal development of antral follicles and ovulation, an overproduction of NGF compromises the ability of antral follicles to reach a preovulatory stage, and thus establishes conditions leading to the development of polycystic ovaries. To accomplish this Aim we will use transgenic mice that overexpress NGF in a cell specific manner, and mice in which signaling through p75 (the common NT receptor), or trkA (the high-affinity NGF receptor) are conditionally disrupted in ovarian cells. 4) To test the hypothesis that an excess of ovarian NGF creates conditions in the local microenvironment that favor the development of polycystic ovaries in nonhuman primates. To accomplish this Aim we will use a lentiviral delivery system to enhance the production of NGF in the interstitial compartment of the adult nonhuman primate ovary.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 关于控制卵巢发育的激素机制已经知道很多。 最近，该领域的一个主要关注焦点是确定 调节途径，在卵巢微环境中运作， 卵巢生殖能力的获得。在这个框架内，我们 一个实验室已经提出了神经营养因子（NT）及其Trk酪氨酸的概念， 激酶受体，长期以来被认为是专门需要的发展， 神经系统也参与控制卵巢功能。就业基因 靶向方法，我们确定了trkB，神经营养因子的高亲和力受体， 4/5（NT-4/5）和脑源性神经营养因子（BDNF）作为信号分子 早期卵泡生长和卵母细胞存活所需的。此外，我们还表明， 神经生长因子（NGF）独立地促进卵泡的启动， 增长其他研究表明，通过trkA受体作用的NGF也很重要 排卵，但尽管这种生理作用，一个不适当的持续 卵巢内NGF合成增加导致功能改变， 卵泡囊肿的发展。根据这些发现，目前的更新 申请提出了以下具体目标：1）定义TrkB受体 早期卵泡生长和卵母细胞存活所需的同种型（全长或截短）， 并鉴定主要响应TrkB信号传导的细胞。本目标的目的 将使用Cre-loxP技术来特异性地破坏 在卵母细胞或颗粒细胞中的全长和截短的TrkB同种型。2)测试 NTs通过TrkB受体信号传导促进早期卵泡生长的假说 通过支持卵母细胞-颗粒细胞Jagged 1-Notch 2通讯途径。 这一目标将通过细胞特异性trkB科斯和 细胞/生物化学方法来定义TrkB之间存在的关系， Notch 2信号通路。3)为了验证神经生长因子- 依赖性trkA信号传导是有腔卵泡正常发育所必需的 和排卵时，过量的NGF会损害有腔卵泡的能力， 达到排卵前阶段，从而建立导致排卵的条件。 多囊卵巢的发育为了实现这一目标，我们将使用转基因小鼠 以细胞特异性方式过表达NGF的小鼠， p75（常见的NT受体）或trkA（高亲和力的NGF受体）是 在卵巢细胞中有条件地破坏。4)为了验证一个假设 卵巢神经生长因子在局部微环境中创造条件， 非人类灵长类动物多囊卵巢的发育。为了实现这一目标，我们 将使用慢病毒传递系统，以提高生产的神经生长因子在 成年非人类灵长类动物卵巢的间质区室。