MECHANISM OF OXYSTEROL ACTIVATION OF MEMBRANE CHOLESTEROL

氧甾醇激活膜胆固醇的机制

• 批准号: 8037963
• 负责人: DANIEL S ORY
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037963
• 关键词: Acute; Adverse effects; Atherosclerosis; Behavior; Cell membrane; Cell physiology; Cells; Cholesterol; Cholesterol Homeostasis; Cholesterol Oxidase; Complex; Cultured Cells; Cyclodextrins; Deuterium; Disease; Drug Delivery Systems; Endoplasmic Reticulum; Environment; Enzymes; Equilibrium; Erythrocytes; Esterification; Fluorescence; Fluorescent Probes; Genetic Transcription; Goals; Hereditary Disease; Hour; Human; Human Genetics; Hydroxymethylglutaryl-CoA reductase; Inborn Errors of Metabolism; Investigation; Label; Lead; Lipid Bilayers; Lipids; Lipoproteins; Liposomes; Measures; Mediating; Membrane; Membrane Lipids; Mitochondria; Modeling; Molecular; Monitor; Pathway interactions; Patients; Phospholipids; Physiological; Positioning Attribute; Predisposition; Proteins; Regulation; Regulatory Pathway; Resolution; Role; Side; Signal Transduction; Solvents; Sterols; Structure; Testing; cholesterol analog; enantiomer; heart disease risk; insight; molecular dynamics; oxidation; research study; response; simulation; solute; trafficking; uptake

DESCRIPTION (provided by applicant): Cellular cholesterol levels are tightly regulated by multiple homeostatic pathways that respond to elevations of membrane cholesterol and to enzymatically formed oxygenated cholesterol derivatives (i.e., oxysterols). Alterations in sterol sensing and trafficking pathways contribute to human inborn errors of metabolism (e.g., Niemann-Pick C disease) and to acquired disease states (e.g., atherosclerosis). Under physiological conditions, sterol-regulated transcriptional pathways act in concert to inhibit uptake of exogenous lipoproteins and suppress de novo cholesterol synthesis, resulting in half-maximal suppression of these responses within several hours. By contrast, pathophysiological cholesterol levels, such as those present in disease states, activate transcription-independent mechanisms that respond within minutes to changes in increments in membrane cholesterol. Recent studies with oxysterol enantiomers provide evidence that sterol-membrane interactions underlie these acute cholesterol homeostatic responses. We hypothesize that side-chain oxysterols serve a critical role in acute regulation of cholesterol homeostasis through direct modulation of plasma membrane lipid environment. We propose that side-chain oxysterols trigger transcription-independent regulatory pathways by disordering membrane phospholipid organization and/or increasing the accessibility of cholesterol. This hypothesis will be tested by the following Specific Aims: (1) Characterization of the mechanism by which oxysterols perturb the structure of model cholesterol-phospholipid bilayers, (2) Examination of the effect of oxysterols on cholesterol accessibility and position in physiological membranes, and (3) Examination of the mechanism by which oxysterols promotes release of plasma membrane cholesterol to intracellular pools. The proposed studies will further our understanding of how perturbations in membrane structure relay cholesterol homeostatic regulatory signals and may identify new pharmacological targets for manipulation of the cellular handling of cholesterol in disease states. PUBLIC HEALTH RELEVANCE: While cholesterol is essential for normal cellular function, alterations in cholesterol metabolism can contribute to human genetic disease and to acquired disease states, such as atherosclerosis. The goal of this study is to understand at the molecular level how cells respond to excess cholesterol and maintain cholesterol balance. The proposed studies may identify new drug targets for treatment of patients with elevated cholesterol levels, who are at risk for heart disease.

描述（由申请人提供）：细胞胆固醇水平受到多种稳态途径的严格调节，所述稳态途径响应于膜胆固醇的升高和酶促形成的氧化胆固醇衍生物（即，氧固醇）。固醇传感和运输途径的改变有助于人类先天性代谢缺陷（例如，尼曼-皮克C病）和获得性疾病状态（例如，动脉粥样硬化）。在生理条件下，甾醇调节的转录途径协同作用，抑制外源性脂蛋白的摄取，抑制从头胆固醇合成，导致在几个小时内这些反应的一半最大抑制。相比之下，病理生理学胆固醇水平，如疾病状态中存在的胆固醇水平，激活转录非依赖性机制，在几分钟内对膜胆固醇增量的变化做出反应。最近的研究与氧固醇对映体提供的证据表明，甾醇膜相互作用的基础，这些急性胆固醇稳态反应。我们推测侧链氧化固醇通过直接调节质膜脂质环境在胆固醇稳态的急性调节中起关键作用。我们认为侧链氧化固醇通过扰乱膜磷脂组织和/或增加胆固醇的可及性来触发转录非依赖性调节途径。该假设将通过以下特定目的进行检验：（1）氧固醇干扰模型胆固醇-磷脂双层结构的机制表征，（2）检查氧固醇对胆固醇可及性和生理膜中位置的影响，以及（3）检查氧固醇促进质膜胆固醇释放至细胞内池的机制。拟议的研究将进一步我们的理解如何在膜结构的扰动中继胆固醇稳态调节信号，并可能确定新的药理学目标，在疾病状态下的胆固醇细胞处理的操作。 公共卫生相关性：虽然胆固醇是正常细胞功能所必需的，但胆固醇代谢的改变可导致人类遗传疾病和获得性疾病状态，如动脉粥样硬化。这项研究的目的是在分子水平上了解细胞如何应对过量的胆固醇并维持胆固醇平衡。拟议的研究可能会确定新的药物靶点，用于治疗胆固醇水平升高的患者，这些患者有患心脏病的风险。