NEURAL CONTROL OF THE PREPUBERTAL OVARY

本申请的总体目标是阐明神经内分泌 参与卵巢功能发育调节的机制。 本文提出了卵巢发育过程中受到一种 互动参与的“神经内分泌营养”控制 外部神经支配，一种神经递质的性腺内来源， 和一个神经营养基因家族，以前认为它们只针对 神经系统的生物学行为。 这个概念源于一个 一系列观察表明：a） 外源性神经支配对卵巢类固醇生成的调节作用， 卵泡发育，B）神经生长因子（NGF）参与 通过其神经营养作用间接调节卵巢发育， 卵巢的神经支配，c）神经递质的能力， 卵巢神经启动分子分化的早期 卵泡生长开始时的颗粒细胞，和d）卵泡中的存在， 灵长类动物卵巢是儿茶酚胺生物合成的内在来源。 进一步的研究表明，卵巢功能的增强， 交感神经支配可能有助于多囊卵巢综合征的病因 卵巢综合征，最常见的卵巢病理影响的妇女， 生育年龄 在研究NGF支持卵巢神经支配的作用时， 很明显，发育中的卵巢不仅合成了几种 神经营养因子的NGF家族成员，但出乎意料的是， 表达酪氨酸激酶受体，其介导生物学过程， 神经营养素在神经系统中的作用。 出现该等 卵巢内分泌细胞中的神经营养因子受体表明， 直接影响卵巢功能，而没有中间的 神经支配，并提出了一个迄今为止有趣的可能性， 神经营养素在控制卵巢发育中的作用。 本申请提出了生理、细胞、免疫和组织化学的组合。 和分子方法来解决这个问题，并定义 每种拟议的“神经内分泌营养”组分对 在卵巢成熟过程中特定发育事件的调节。 到 为此，提出以下具体目标：1.审查 假设两种神经营养因子，NGF和神经营养因子-4， 但在细胞分化/组织过程中的互补作用 在确定的卵巢组织发生时期， 滤泡形成 2.为了验证神经递质 和神经营养因子积极地相互作用， 卵泡发育早期颗粒细胞的分化。 3.为了检验在细胞凋亡过程中trkA受体的激活 第一次排卵前10小时有助于细胞分化 导致卵泡破裂。 4.为了检验这个假设， 卵巢NGF合成及其低亲和力受体的激活 是多囊卵巢综合征病因的关键组成部分。 5.到 表征酪氨酸的分子形式和细胞来源 羟化酶和多巴胺-β羟化酶，两个关键酶， 最近发现，儿茶酚胺合成在发育中表达， 灵长类卵巢

The overall goal of this application is to elucidate the neuroendocrine mechanisms involved in the developmental regulation of ovarian function. The concept is proposed that the developing ovary is subjected to a "neuroendocrinotrophic" control effected by the interactive participation of the extrinsic innervation, an intragonadal source of neurotransmitters, and a family of neurotrophic genes previously believed to target only the nervous system for their biological actions. This concept stems from a series of observations demonstrating: a) the contribution of the extrinsic innervation to the regulation of ovarian steroidogenesis and follicular development, b) the involvement of nerve growth factor (NGF) in regulating ovarian development indirectly via its neurotrophic effects on the ovarian innervation, c) the ability of neurotransmitters contained in ovarian nerves to initiate the molecular differentiation of early granulosa cells at the onset of follicular growth, and d) the existence in the primate ovary of an intrinsic source of catecholamine biosynthesis. Further studies suggested that an enhanced activity of the ovarian sympathetic innervation may contribute to the etiology of polycystic ovarian syndrome, the most common ovarian pathology affecting women of reproductive age. While studying the role of NGF in supporting the ovarian innervation, it became apparent that the developing ovary not only synthesizes several members of the NGF family of neurotrophins, but unexpectedly, also expresses the tyrosine kinase receptors that mediate the biological actions of neurotrophins in the nervous system. The presence of such receptors in endocrine cells of the ovary implies that neurotrophins can directly affect ovarian function without the intermediacy of the innervation, and raises the intriguing possibility of an hitherto unsuspected role for neurotrophins in the control of ovarian development. The present application proposes a combination of physiological, cellular and molecular approaches to address this issue, and to define the contribution of each of the proposed "neuroendocrinotrophic" components to the regulation of specific developmental events in ovarian maturation. To this end, the following specific aims are proposed: 1. To examine the hypothesis that two neurotrophins, NGF and neurotrophin-4, play different, but complementary roles in the cytodifferentiation/ organizational process underlying the period of definitive ovarian histogenesis, at the time of follicular formation. 2. To examine the hypothesis that neurotransmitters and neurotrophins interact positively in promoting the molecular differentiation of granulosa cells during early follicular development. 3. To examine the hypothesis that activation of trkA receptors during the hours preceding the first ovulation contributes to the cytodifferentiation process leading to follicular rupture. 4. To examine the hypothesis that activation of ovarian NGF synthesis and that of its low-affinity receptor is a key component in the etiology of polycystic ovarian syndrome. 5. To characterize the molecular forms and cellular sources of tyrosine hydroxylase and dopamine-beta hydroxylase, the two key enzymes in catecholamine synthesis recently found to be expressed in the developing primate ovary.