NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

这是一个旨在阐明神经内分泌机制的应用。 参与控制哺乳动物青春期的开始。自.以来 作为1977年一个方案项目的一部分，最初的提议开始了， 我们朝着这一目标稳步前进，首先描绘了 不同的脑下垂体和性腺激素在调控中的作用 女性的性发育，然后定义类固醇的贡献 促性腺激素发育调控的反馈机制 释放，然后，表征信号转导通路 参与神经递质诱导的LHRH释放过程 青春期。进一步的研究得出了这样的结论-LHRH神经元 它们本身并不构成青春期发生的限制因素， 激活LHRH神经元的兴奋性输入是主要的 导致女性青春期开始的机制。这些和其他 提出了一些宝贵的意见，即必须努力确定 “上游‘分子成分，在大脑内运作， 确定青春期进程的启动。在上一期内 我们获得了与转化生长因子有关的证据 Alpha(Turk.)，表皮生长因子(EGF)家族成员，AS 这些组件之一。星形胶质细胞的鉴定 血统作为TGFα合成的主要来源，导致了额外的 表明存在神经元神经胶质相互作用事件的研究 以及神经胶质衍生分子在发育过程中的作用 LHRH神经元功能的控制。本申请提出了 研究坚定地确定了高血压的性质和生理重要性 这些互动。它还打算确定更高水平的 控制青春期开始的神经内分泌级联中的等级 通过表征调控同源异型盒的潜在参与- 编码基因在青春期过程中的控制。为此， 提出了以下目标：1)检验胶质细胞转化生长因子-1的假设。 Alpha通过诱导前列腺素E间接刺激LHRH释放 (PGE2)从星形胶质细胞释放，并通过选择性上调，也通过 与钙离子相关的PGE2受体基因的表达 LHRH神经元的动员和/或环磷酸腺苷的形成。2)审查 转化生长因子-α基因在下丘脑星形胶质细胞中的表达不仅 受神经胶质起源的旁分泌/自分泌影响而上调，但也受 一些相同的神经递质输入刺激LHRH的分泌 在青春期。3)检验以下假设： EGF/TGR-α家族与转化生长因子-α在 LHRH神经元功能的控制，以及4)检验假设 新发现的POU结构域基因家族同源异型盒基因Oct-2 在损毁诱导性行为的雌性大鼠下丘脑中发现 早熟，有助于转化生长因子-α的转录激活 基因，因此代表了上游调控基因之一 控制青春期的开始。

This is an application aimed at elucidating the neuroendocrine mechanisms involved in controlling the initiation of mammalian puberty. Since the inception of the original proposal, as part of a program project in 1977, we have made steady progress towards this goal, first delineating the roles that different pituitary and gonadal hormones play in the control of female sexual development, then defining the contribution of steroid feedback mechanisms to the developmental regulation of gonadotropin release, and later, characterizing the signal transduction pathways involved in the process of neurotransmitter-induced LHRH release at puberty. Further studies led to the conclusion-that LHRH neurons themselves do not constitute a limiting factor for puberty to occur, and that an activation of excitatory inputs to LHRH neurons is a primary mechanism contributing to the onset of female puberty. These and other observations made dear that efforts had to be devoted to identifying "upstream' molecular components that, operating within the brain, determine the initiation of the pubertal process. During the last period of support, we obtained evidence implicating transforming growth factor alpha (TURK.), a member of the epidermal growth factor (EGF) family, as one of these components. Identification of glial cells of the astrocytic lineage as the main source of TGFalpha synthesis, led to additional studies that suggested the existence of neuronal glial interactive events and the participation of glial-derived molecules in the developmental control of LHRH neuronal function. The present application proposes studies to firmly define the nature and the physiological importance of these interactions. It also intends to identify a higher level of hierarchy in the neuroendocrine cascade that controls the onset of puberty by characterizing the potential involvement of a regulatory homeobox- encoding gene in the control of the pubertal process. To this end, the following aims are proposed: 1) To examine the hypothesis that glial TGF- alpha stimulates LHRH release indirectly by eliciting prostaglandin E (PGE2) release from astrocytes and by selectively upregulating, also via glial intermediacy, the expression of PGE2 receptor genes linked to Ca2+ mobilization and/or cyclic AMP formation in LHRH neurons. 2) To examine the that TGF-alpha gene expression in hypothalamic astrocytes is not only upregulated by paracrine/autocrine influences of glial origin, but also by some of the same neurotransmitter inputs known to stimulate LHRH secretion at puberty. 3) To examine the hypothesis that other members of the EGF/TGR-alpha family interact collaboratively with TGF-alpha in the control of LHRH neuronal function, and 4) To examine the hypothesis that Oct-2, a homeobox-containing gene of the POU-domain gene family recently found in the hypothalamus of female rats undergoing lesion-induced sexual precocity, contributes to the transcriptional activation of the TGF-alpha gene and, hence, represents one of the upstream regulatory genes controlling the onset of puberty.