Regulation of GnRH receptor signaling by lipid rafts

脂筏对 GnRH 受体信号传导的调节

• 批准号: 6885387
• 负责人: Stuart Bliss
• 金额: $ 6.77万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-18 至 2006-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885387
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; cell line; cholesterol; flow cytometry; genetically modified animals; gonadotropin releasing factor; hormone receptor; hormone regulation /control mechanism; laboratory mouse; lipids; mitogen activated protein kinase; northern blottings; polymerase chain reaction; postdoctoral investigator; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) exerts its biological effects by binding to its cognate receptor on the surface of pituitary gonadotropes and stimulating the synthesis and secretion of luteinizing hormone and follicle-stimulating hormone. At the molecular level, engagement of the GnRH receptor initiates a complex series of signaling events including activation of the mitogen-activated protein kinase (MAPK) pathways; this activation is required for the induction of several genes essential for gonadotrope function. Understanding the regulation of GnRH-induced MAPK signaling is thus of great importance in reproductive endocrinology. One mechanism by which signaling pathways are regulated involves subcellular compartmentalization of signaling molecules through their association with specialized plasma membrane domains called lipid rafts. Lipid rafts are cholesterol and sphingolipid rich membrane domains with distinct biophysical properties that have been shown to function as platforms for the assembly of multi-protein signaling complexes. Here we provide preliminary evidence that the GnRH receptor as well as key MAPK signaling molecules are associated with lipid rafts in the murine alphaT3-1 gonadotrope cell line. This proposal outlines a set of experiments designed to test the hypothesis that lipid rafts regulate GnRH-induced MAPK signaling in gonadotropes by facilitating the compartmentalized assembly of definable MAPK signaling modules. We will use a variety of biochemical, molecular, and cell-biological techniques to study the role of lipid rafts in GnRH-induced MAPK signaling both in alphaT3-1 cells, as well as in primary differentiated mouse gonadotropes.

描述（申请人提供）：促性腺激素释放激素（GnRH）通过与垂体促性腺激素表面的同源受体结合，刺激促黄体生成素和促卵泡激素的合成和分泌，发挥其生物学作用。在分子水平上，GnRH受体的参与启动了一系列复杂的信号事件，包括丝裂原活化蛋白激酶（MAPK）途径的激活；这种激活是诱导促性腺激素功能所必需的几个基因所必需的。因此，了解gnrh诱导的MAPK信号的调控在生殖内分泌学中具有重要意义。信号通路调控的一种机制涉及信号分子的亚细胞区隔化，通过它们与称为脂筏的特殊质膜结构域的关联。脂筏是富含胆固醇和鞘脂的膜结构域，具有独特的生物物理特性，已被证明是多蛋白信号复合物组装的平台。在这里，我们提供了GnRH受体以及关键的MAPK信号分子与小鼠α -1促性腺激素细胞系中的脂筏相关的初步证据。本提案概述了一系列实验，旨在验证脂筏通过促进可定义的MAPK信号模块的区隔组装来调节促性腺激素中gnrh诱导的MAPK信号传导的假设。我们将使用多种生化、分子和细胞生物学技术来研究脂筏在gnrh诱导的MAPK信号传导中的作用，包括在alpha -1细胞中，以及在原代分化的小鼠促性腺激素中。