Regulatory Roles of Cellular Cholesterol

细胞胆固醇的调节作用

• 批准号: 8671006
• 负责人: WONHWA CHO
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671006
• 关键词: Address; Affect; Alzheimer' s Disease; Antineoplastic Agents; Binding; Biological Process; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Cholesterol; DLG1 gene; DLG4 gene; Databases; Diagnosis; Disease; Health; Image; Imaging technology; In Situ; Integral Membrane Protein; Laboratories; Link; Lipids; Mammalian Cell; Measures; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Metabolism; Phosphatidylinositol 4,5-Diphosphate; Play; Principal Investigator; Proteins; Proteomics; Regulation; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Stimulus; System; Technology; Testing; Time; base; cell growth regulation; cellular imaging; cholesterol-binding protein; drug development; fluorescence imaging; genetic regulatory protein; human disease; innovation; novel strategies; phosphatidylinositol phosphate, PtdIns(4,5)P2; physical property; prevent; programs; public health relevance; response; sensor; spatiotemporal; tool

PROJECT DESCRIPTION Cholesterol is a major lipid component of the mammalian plasma membrane. Abnormal cholesterol levels have been implicated in several diseases, including cardiovascular diseases, Niemman-Pick type C disease, and Alzheimer's disease, among others; however it is not know how the cholesterol concentration is linked to cellular processes. In particular, the direct involvement of cholesterol in cell regulation through specific interactions with cytosolic proteins has not been thoroughly investigated. We have recently discovered that cholesterol specifically interacts with various cytosolic scaffold proteins and regulate their diverse cellular signaling activities. This important finding not only demonstrates that cholesterol can directly interact with major cellular regulatory proteins but also offers excellent systems to investigate the direct correlation between membrane cholesterol levels and cellular activities. We also developed a new fluorescence imaging technology for accurate in situ real-time quantification of membrane lipids. Collectively, our discovery of a new class of cholesterol binding proteins and our new quantitative lipid imaging technology provide us a unique and unprecedented opportunity to systematically study the mechanisms by which cholesterol regulates diverse cellular processes. Our main hypothesis is that the local cholesterol level in the plasma membrane serves as an activation threshold for various cellular processes, including Wnt signaling. The primary objective of this proposed research is to investigate the mechanisms underlying diverse cholesterol-mediated cell regulation. Specifically, we propose to (1) determine how cholesterol regulates Wnt signaling through specific interaction with a scaffold protein, Dvl, (2) establish robust and versatile in situ quantitative imaging of cellular cholesterol, and (3) determine how changes in the local cholesterol level in the plasma membrane mediate canonical Wnt signaling.

项目描述 胆固醇是哺乳动物质膜的主要脂质成分。异常胆固醇 水平与多种疾病有关，包括心血管疾病，Niemman-Pick C型疾病和阿尔茨海默氏病等；但是不知道胆固醇是如何 浓度与细胞过程有关。特别是，胆固醇直接参与细胞 通过与胞质蛋白的特定相互作用进行调节尚未得到彻底研究。 我们最近发现，胆固醇专门与各种胞质支架相互作用 蛋白质并调节其多种细胞信号传导活性。这个重要的发现不仅 证明胆固醇可以直接与主要的细胞调节蛋白相互作用，但也可以 提供了出色的系统来研究膜胆固醇水平之间的直接相关性 和细胞活动。我们还开发了一种新的荧光成像技术，以精确原位 膜脂质的实时定量。总体而言，我们发现了一类新的胆固醇 具有约束力的蛋白质和我们的新定量脂质成像技术为我们提供了独特的和 前所未有的机会，可以系统地研究胆固醇调节的机制 各种细胞过程。我们的主要假设是血浆中的局部胆固醇水平 膜是各种细胞过程（包括Wnt信号传导）的激活阈值。 这项拟议的研究的主要目的是研究多样化的机制 胆固醇介导的细胞调节。具体来说，我们建议（1）确定胆固醇 通过与脚手架蛋白DVL的特定相互作用来调节Wnt信号传导，（2）建立可靠的 和多功能的原位定量成像对细胞胆固醇的原位成像，（3）确定如何变化 质膜中的局部胆固醇水平介导规范的Wnt信号传导。