NEURAL CONTROL OF THE PREPUBERTAL OVARY

青春期前卵巢的神经控制

基本信息

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
项目类别：
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

项目摘要

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.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。人们对控制卵巢发育的激素机制了解很多。最近，该领域关注的一个主要焦点是识别在卵巢微环境中运作的调节途径，有助于从而获得卵巢的生殖能力。在这个框架内，我们的实验室提出了神经营养素 (NT) 及其 Trk 酪氨酸的概念激酶受体，长期以来被认为是细胞发育所必需的神经系统也参与卵巢功能的控制。用人基因我们确定了 trkB 的靶向方法，trkB 是神经营养素的高亲和力受体 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）独立地促进卵泡的形成生长。其他研究表明 NGF 通过 trkA 受体发挥作用也很重要排卵，但尽管有这种生理作用，但不适当的持续卵巢内 NGF 合成的增加导致功能改变，从而导致毛囊囊肿的发展。基于这些发现，目前的更新申请提出以下具体目标： 1) 定义 TrkB 受体早期卵泡生长和卵母细胞存活所需的亚型（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 通过 TrkB 受体信号传导促进早期卵泡生长的假设通过支持卵母细胞到颗粒细胞的锯齿状 1-Notch2 通讯途径。这一目标将通过结合使用细胞特异性 trkB KO 和细胞/生化方法来定义 TrkB 之间存在的关系信号传导和 Notch2 通路。 3) 检验以下假设：虽然 NGF- 窦卵泡的正常发育需要依赖的 trkA 信号传导和排卵期间，NGF 的过量产生会损害窦卵泡的能力达到排卵前阶段，从而创造了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度表达 NGF 的小鼠，以及通过信号传递的小鼠 p75（常见 NT 受体）或 trkA（高亲和力 NGF 受体）卵巢细胞有条件地受到破坏。 4) 检验过量的假设卵巢NGF在局部微环境中创造有利于生长的条件非人类灵长类动物多囊卵巢的发育。为了实现这个目标我们将使用慢病毒传递系统来增强 NGF 的产生成年非人类灵长类动物卵巢的间质室。