BRAIN OXYTOCIN RECEPTORS--FUNCTION AND STRUCTURE

脑催产素受体——功能和结构

• 批准号: 2858035
• 负责人: Lori Marie Flanagan-Cato
• 金额: $ 11.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2858035
• 关键词: RNase protection assay; behavioral /social science research tag; estradiol; female; genetic transcription; hormone regulation /control mechanism; hypothalamus; laboratory rat; molecular cloning; northern blottings; nuclear runoff assay; nucleic acid sequence; oxytocin; polymerase chain reaction; progesterone; progesterone receptors; protein structure function; radionuclides; receptor binding; receptor expression; second messengers; sex behavior; steroid hormone receptor; tissue /cell culture; transfection; western blottings

DESCRIPTION (Adapted from applicant's abstract): This is a revised application for a FIRST award (R29). My long-term research goal is to establish an independent multidisciplinary research program to reveal the mechanisms whereby ovarian steroid hormones regulate female sexual behavior in rats. This behavior has long served as an excellent model system for the biological basis of steroid hormone actions in brain. Previous studies have shown that oxytocin receptors (OTRs) in the hypothalamus facilitate female sexual behavior after pretreatment with estradiol and progesterone. Estradiol appears important for enhancing the level of mRNA for this protein. In the absence of progesterone, however, these estradiol-induced receptors are not sufficient for OT to augment sexual behavior. The mechanism of progesterone's permissive effects are not known. The proposed experiments will examine the mechanisms of estradiol and progesterone regulation of OTR expression and function in the rat brain. The first specific aim is to clone OTRs from rat brain. This is expected to enable the investigators to develop the appropriate reagents (e.g., probes, antisera) for subsequent studies. The second specific aim is to test the hypothesis that estradiol and progesterone regulate OTR transcripts by modulating the rate of transcription. This study will not only determine the mechanism for estradiol-induced increases in OTR mRNA, but will also determine whether progesterone actively co-regulates estradiol's effects on OTR transcription. The third specific aim will test the hypothesis that steroid hormone-induced changes in OTR binding activity in the hypothalamus are associated with alteration in second messenger production. For example, the hypothesis will be tested that the biological basis for progesterone-dependent facilitation of sexual behavior by OT is the augmentation of OTR signal transduction. A final inquiry will determine whether any increases in OTR signal transduction are mediated in part by steroid hormone-induced upregulation of G proteins associated with OTRs. Taken together, the proposed experiments will provide a detailed analysis of the multiple levels of regulation by steroid hormones of this neuropeptide receptor to permit plasticity of this biologically important behavior. Insights gained from these studies may be relevant to other examples of steroid interactions with neural circuits, such as stress responses and mood disorders.

描述(改编自申请人的摘要)：这是一份修订后的 申请一等奖(R29)。我的长期研究目标是 建立独立的多学科研究计划，以揭示 卵巢类固醇激素调节女性性行为的机制 在老鼠身上。长期以来，这一行为一直是 类固醇激素在大脑中作用的生物学基础。之前的研究已经 研究表明，下丘脑中的催产素受体(OTRs)有助于女性 雌二醇孕酮预处理后的性行为。 雌二醇似乎对提高这方面的基因水平很重要。 蛋白。然而，在没有黄体酮的情况下，这些雌激素诱导 受体不足以让催产素增加性行为。这个 黄体酮的允许作用机制尚不清楚。建议数 实验将研究雌激素和黄体酮的作用机制。 大鼠脑内OTR表达和功能的调节。第一 其具体目的是从大鼠脑中克隆OTRs。预计这将使 研究人员开发适当的试剂(例如，探针， 抗血清)，用于后续研究。第二个具体目标是测试 雌激素和孕酮通过以下途径调节OTR转录的假说 调节转录速度。这项研究不仅将确定 雌激素诱导OTRmRNA增加的机制，但也将 确定黄体酮是否主动地共同调节雌二醇对 Otr转录。第三个具体目标将检验以下假设 类固醇激素引起的下丘脑OTR结合活性的变化 与第二信使生产中的变化有关。例如, 这一假说将得到检验，即 催产素对性行为的促进作用依赖于孕激素 OTR信号转导的增强。最终调查将确定 OTR信号转导的增加是否在一定程度上通过 类固醇激素诱导与OTRs相关的G蛋白上调。 综上所述，拟议的实验将提供对 类固醇激素对该神经肽的多水平调节 受体允许这种生物重要行为的可塑性。 从这些研究中获得的见解可能与其他例子有关 类固醇与神经回路的相互作用，如应激反应和情绪 精神错乱。