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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 关于控制卵巢发育的激素机制知之甚少。 最近，该领域的主要关注重点是确定 在卵巢微环境内运行的监管途径贡献 获得卵巢生殖能力。在这个框架内，我们 实验室已经发展了神经营养蛋白（NTS）及其TRK酪氨酸的概念 激酶受体，长期以来被认为是开发的仅需要的 神经系统还参与了卵巢功能的控制。使用基因 我们确定的靶向方法TRKB，神经营养蛋白的高亲和力受体 4/5（NT-4/5）和脑衍生的神经营养因子（BDNF）作为信号分子 早期卵泡生长和卵母细胞存活所必需的。此外，我们证明了 神经生长因子（NGF）独立贡献卵泡 生长。其他研究表明，NGF通过TRKA受体作用也很重要 对于排卵 沃里安内NGF合成的增加导致功能改变导致 卵泡囊肿的发展。基于这些发现，目前的续约 应用提出以下特定目的：1）定义TRKB受体 早期卵泡生长和卵母细胞存活所需的同工型（全长或截短）， 并确定主要响应TRKB信号传导的细胞。这个目标的目标 将使用Cre-loxp技术来特异性破坏 卵母细胞或颗粒细胞中的全长和截短的TRKB同工型。 2）测试 NTS信号通过TRKB受体促进早期卵泡生长的假设 通过支持卵母细胞到颗粒细胞锯齿状1-Notch2通信途径。 通过组合特异性TRKB KOS和 细胞/生化方法来定义TRKB之间存在的关系 信号传导和Notch2途径。 3）测试虽然NGF-的假设 依赖的TRKA信号是肛门卵泡的正常发育所必需的 和排卵，NGF的过量生产损害了肛门卵泡的能力 到达排卵阶段，因此建立了导致的条件 多囊卵巢的发展。为了实现这一目标，我们将使用转基因小鼠 以细胞特定方式过表达NGF，而小鼠则通过发出信号的小鼠 p75（公共NT受体）或TRKA（高亲和力NGF受体）是 有条件地在卵巢细胞中破坏。 4）检验过多的假设 卵巢NGF在当地微环境中创造条件，有利于 非人类灵长类动物中多囊卵巢的发展。为了实现这一目标 将使用慢病毒输送系统来增强NGF的生产 成年非人类灵长类动物卵巢的间质室。