Steroid Hormones Regulatory Mechanisms and Behavior

类固醇激素的调节机制和行为

• 批准号: 6916258
• 负责人: SHAILAJA K MANI
• 金额: $ 31.36万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916258
• 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.

性状（由申请人提供）：卵巢类固醇激素，雌二醇 和孕酮，调节中枢神经系统的细胞功能 导致各种各样的生理和生殖行为的变化， 物种对性行为的预后影响不仅通过 涉及细胞内核的“经典”基因组作用机制 受体，但也通过快速的“非经典”途径，涉及核外 信号转导级联。虽然细胞和分子机制 参与这两种机制的融合还没有很好地理解，它 可能涉及蛋白激酶依赖的信号转导之间的“串扰” 级联反应起始于细胞膜和核转录因子。 通过蛋白激酶级联实现的显著信号放大可以 改变神经元细胞内的磷酸化动力学， 产生多组分但协调的协同或冗余效应 分子反应，最终导致统一的行为结果。这项建议 侧重于确定孕酮作用的机制， 超出了经典的细胞内类固醇受体介导的途径。 特别是，我们建议确定生物化学和分子事件 这是快速甾醇启动的信号转导途径的基础。 具体目标1将确定快速、 与脊柱前凸相关的区域中的孕酮启动信号。我们将 检验孕酮引发的cAMP增加激活 下丘脑和下丘脑中的有丝分裂原活化蛋白激酶（MAPK）途径 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 下游核转录靶点如Ca+2/cAMP的磷酸化 反应元件结合蛋白（CREB）。具体目标2将决定 通过检查活化的MAPK级联的细胞内定位， p-MAPK及其下游效应物在细胞水平的分布。 具体目标3将检验以下假设： MAPK介导的级联反应及其转录靶点介导性行为 in vivo.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 大脑行为机制