NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

这是一个旨在阐明神经内分泌机制的应用程序 参与控制哺乳动物青春期的开始。以来 最初的建议，作为1977年计划项目的一部分， 我们在这方面取得了稳步进展，首先划定了 不同的垂体和性腺激素在控制 女性性发育，然后定义类固醇的贡献 促性腺激素发育调节的反馈机制 释放，后来，表征信号转导途径 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结论-LHRH神经元 本身并不构成青春期发生的限制因素， LHRH神经元兴奋性输入的激活是 促进女性青春期开始的机制。这些和其他 提出的宝贵意见认为，必须努力查明 “上游”分子成分，在大脑中运作， 决定青春期的开始 在上一个时期， 支持，我们获得的证据表明，转化生长因子 alpha（土耳其），表皮生长因子（EGF）家族的成员，如 这些组件之一。星形胶质细胞胶质细胞的鉴定 作为TGF α合成的主要来源， 研究表明存在神经胶质相互作用事件， 以及神经胶质衍生的分子在发育过程中的参与 LHRH神经元功能的控制。本申请提出 研究，以坚定地定义的性质和生理重要性， 这些互动。它还打算确定一个更高级别的 控制青春期开始的神经内分泌级联中的层次结构 通过表征调控同源框的潜在参与- 编码基因在控制青春期过程中的作用。为此中央 本研究的主要目的是：1）研究胶质细胞TGF-β 1表达的可能性。 α通过诱发前列腺素E间接刺激LHRH释放 （PGE 2）从星形胶质细胞释放，并通过选择性上调，也通过 胶质细胞中介性，与Ca 2+相关的PGE 2受体基因的表达 动员和/或环AMP形成的LHRH神经元。2)审查 下丘脑星形胶质细胞中TGF-α基因表达不仅 上调的旁分泌/自分泌的影响，神经胶质起源，但也 一些已知刺激LHRH分泌的相同神经递质输入 在青春期。3)为了检验这个假设， EGF/TGR-α家族与TGF-α协同作用 LHRH神经元功能的控制，以及4）为了检验以下假设， Oct-2是POU结构域基因家族中的一个同源框基因， 在雌性大鼠的下丘脑中发现， 早熟，有助于TGF-α的转录激活， 基因，因此代表上游调控基因之一 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.