Steroid Hormones Regulatory Mechanisms and Behavior

类固醇激素的调节机制和行为

• 批准号: 6479793
• 负责人: SHAILAJA K MANI
• 金额: $ 32.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479793
• 关键词: behavioral /social science research tag; biological signal transduction; cAMP response element binding protein; calcium ion; cyclic AMP; female; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; laboratory mouse; laboratory rat; mitogen activated protein kinase; neuroendocrine system; oligonucleotides; phosphorylation; progesterone; progesterone receptors; protein localization; sex behavior

DESCRIPTION (provided by applicant): The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in changes in physiology and reproductive behavior in a variety of species. Progesterone effects on sexual behavior are mediated not only through the "classical" genomic mechanism of action involving the intracellular nuclear receptors, but also via rapid "non-classical" pathways involving extra-nuclear signal transduction cascades. While the cellular and molecular mechanisms involved in the convergence of these two mechanisms are not well understood, it could involve "cross-talk" between protein kinase-dependent signal transduction cascades initiated at the membrane and the nuclear transcription factors. Pronounced signal amplification achieved by the protein kinase cascades could alter phosphorylation dynamics within the neuronal cells to achieve additive, synergistic or redundant effects producing a multi-component, but coordinated molecular response, culminating in an unified behavioral outcome. This proposal focuses on the determination of the mechanisms of progesterone action that extend beyond the classical intracellular steroid receptor-mediated pathways. In particular, we propose to determine the biochemical and molecular events underlying the rapid progesterone-initiated signal transduction pathway(s). Specific aim 1 will determine the mechanism underlying the rapid, progesterone-initiated signaling in areas associated with lordosis. We will test the hypothesis that the progesterone-initiated increases in cAMP activate mitogen activated protein kinase (MAPK) pathway in the hypothalamus and preoptic area (POA), the regions known to be associated with lordosis circuitry. We will determine whether activation of MAPK pathway results in the phosphorylation of downstream nuclear transcriptional targets like Ca+2/cAMP response element binding protein (CREB). Specific aim 2 will determine the intracellular localization of the activated MAPK cascade by examining the distribution of p-MAPK and its down-stream effectors at the cellular level. Specific aim 3 will test the hypothesis that the progesterone-activated MAPK-mediated cascade and its transcriptional targets mediate sexual behavior in vivo. Identification of such cross-talk signaling mechanisms will contribute to our understanding of the environmental and internal determinants of hormone-brain-behavior mechanisms.

描述（由申请人提供）：卵巢类固醇激素，雌二醇 和黄体酮，调节中枢神经系统的细胞功能 导致多种生理和生殖行为的变化 物种。黄体酮对性行为的影响不仅通过 涉及细胞内核的“经典”基因组作用机制 受体，但也通过涉及核外的快速“非经典”途径 信号转导级联。虽然细胞和分子机制 这两种机制的融合还没有被很好地理解， 可能涉及蛋白激酶依赖性信号转导之间的“串扰” 级联在膜和核转录因子处启动。 蛋白激酶级联实现的显着信号放大可以 改变神经元细胞内的磷酸化动力学以实现加性， 产生多成分但协调的协同或冗余效应 分子反应，最终形成统一的行为结果。这个提议 重点是确定黄体酮作用机制 超出了经典的细胞内类固醇受体介导的途径。 特别是，我们建议确定生化和分子事件 是孕激素快速启动的信号转导途径的基础。 具体目标 1 将确定快速、 黄体酮在与脊柱前凸相关的区域启动信号传导。我们将 检验黄体酮引发的 cAMP 增加激活的假设 下丘脑有丝分裂原激活蛋白激酶 (MAPK) 通路 视前区 (POA)，已知与脊柱前凸相关的区域 电路。我们将确定 MAPK 通路的激活是否会导致 下游核转录靶标（如 Ca+2/cAMP）的磷酸化 反应元件结合蛋白（CREB）。具体目标 2 将确定 通过检查激活的 MAPK 级联的细胞内定位 p-MAPK 及其下游效应子在细胞水平的分布。 具体目标 3 将检验黄体酮激活的假设 MAPK 介导的级联及其转录靶标介导性行为 体内。识别这种串扰信号机制将有助于 我们对环境和内部决定因素的理解 激素-大脑-行为机制。