Functional Analysis of ACAT

ACAT的功能分析

• 批准号: 7774362
• 负责人: Ta Yuan CHANG
• 金额: $ 39.55万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774362
• 关键词: 7,7-azocholestanol; Abbreviations; Acyl Coenzyme A; Acyltransferase; Affect; Alzheimer disease prevention; Alzheimer' s Disease; American; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anabolism; Animals; Apolipoprotein E; Aspartate; Atherosclerosis; Binding; Binding Proteins; Biological Assay; Biological Process; Brain; Brain Diseases; Cell Culture System; Cell membrane; Cells; Characteristics; Chinese Hamster; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chylomicrons; Coenzyme A; Coenzymes; Complement component C1s; Cyclodextrins; Cysteine; Development; Dimerization; Dimethyl Sulfoxide; Disease; Drug Delivery Systems; Edetic Acid; Endoplasmic Reticulum; Enzymes; Esters; Estradiol; Family; Foam Cells; Genes; Grant; High Pressure Liquid Chromatography; Hyperlipidemia; Immunoglobulins; In Vitro; Integral Membrane Protein; Intervention; Knock-out; Knowledge; Lesion; Lipids; Maleimides; Mammals; Mass Fragmentography; Membrane; Messenger RNA; Modeling; Mus; N-Methylaspartate; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Ovary; Pathogenesis; Pharmacologic Substance; Phenanthrolines; Phosphate Buffer; Play; Polyacrylamide Gel Electrophoresis; Polyethylene Glycols; Polymerase Chain Reaction; Population; Pregnenolone; Proteins; RNA; Regulatory Element; Research; Research Personnel; Role; Saline; Senile Plaques; Site; Sodium Dodecyl Sulfate-PAGE; Sterol O-Acyltransferase; Sterols; Testing; Therapeutic Intervention; Thin Layer Chromatography; Tissues; Transgenic Organisms; Transmembrane Domain; Untranslated Regions; Very low density lipoprotein; biochemical model; dehydroepiandrosterone; diacylglycerol O-acyltransferase; gamma-Aminobutyric Acid; improved; inhibitor/antagonist; lauroyl-coenzyme A; macrophage; member; mouse model; programs; sterol O-acyltransferase 1; sterol O-acyltransferase 2

DESCRIPTION (provided by applicant): Acyl-coenzyme Axholesterol acyltransferase (ACAT) is a membrane-bound enzyme present in a variety of tissues and cells. Using long-chain fatty acyl-coenzyme A and cholesterol as its substrates, ACAT catalyzes the biosynthesis of cholesteryl esters, which comprise part of the neutral lipid cargo packaged into the cores of very low-density lipoproteins and chylomicrons. Under pathophysiological conditions, in cholesterol-loaded macrophages, ACAT converts excess cholesterol into cholesteryl esters. This action reduces the amount of cholesterol available for efflux and converts the macrophages to foam cells, which are the hallmark of early lesions of atherosclerosis. In mammals, two Acat genes exist that encode for two similar but different proteins, ACAT1 and ACAT2. Both enzymes are potential drug targets for pharmaceutical intervention against diseases including atherosclerosis and hyperlipidemia. Recent evidence suggests that ACAT may also be a potential drug target for treating Alzheimer's disease (AD). The long-term objective of this research is to understand the functions of ACAT in vitro, in intact cells, and in animals. For the current proposal, there are two specific aims. The first aim is to test certain key features of a biochemical model proposed to explain ACAT1 as an allosteric enzyme. The second aim is to determine the pathophysiological role of ACAT in a mouse model for AD. The outcome of the first specific aim will provide the first biochemical model for ACAT; this model will help increase our understanding of the mechanisms of actions of ACAT inhibitors. The outcome of the second specific aim will help determine the pathophysiological role of ACAT in a major neurodegenerative disease. This project aims to build a biochemical model for ACAT1, an enzyme critical to cholesterol metabolism, transport, and storage. Knowledge of how ACAT behaves and is inhibited, as well as what role it may play in the development of Alzheimer's disease in a mouse model, can improve our understanding of the causes and prevention of Alzheimer's disease, a progressive brain disorder that affects an estimated 4.5 million Americans and is becoming increasingly common in the U.S. population.

描述（申请人提供）：酰基辅酶Axholesterol酰基转移酶（ACAT）是一种存在于多种组织和细胞中的膜结合酶。使用长链脂肪酰基辅酶A和胆固醇作为其底物，ACAT催化胆固醇酯的生物合成，胆固醇酯构成包装到极低密度脂蛋白和乳糜微粒核心中的中性脂质货物的一部分。在病理生理条件下，在胆固醇负载的巨噬细胞中，ACAT将过量的胆固醇转化为胆固醇酯。这种作用减少了可用于流出的胆固醇的量，并将巨噬细胞转化为泡沫细胞，这是动脉粥样硬化早期病变的标志。在哺乳动物中，存在两个Acat基因，编码两种相似但不同的蛋白质，ACAT 1和ACAT 2。这两种酶是潜在的药物靶点，用于药物干预疾病，包括动脉粥样硬化和高脂血症。最近的证据表明，ACAT也可能是治疗阿尔茨海默病（AD）的潜在药物靶点。本研究的长期目标是了解ACAT在体外、完整细胞和动物中的功能。目前的建议有两个具体目标。第一个目的是测试生化模型的某些关键特征，该模型被提出来解释ACAT 1作为变构酶。第二个目的是确定ACAT在AD小鼠模型中的病理生理作用。第一个具体目标的结果将为ACAT提供第一个生化模型;该模型将有助于增加我们对ACAT抑制剂作用机制的理解。第二个具体目标的结果将有助于确定ACAT在主要神经退行性疾病中的病理生理作用。该项目旨在为ACAT 1建立一个生化模型，ACAT 1是一种对胆固醇代谢，运输和储存至关重要的酶。了解ACAT的行为和被抑制的方式，以及它在小鼠模型中阿尔茨海默病的发展中可能发挥的作用，可以提高我们对阿尔茨海默病的原因和预防的理解，阿尔茨海默病是一种进行性脑部疾病，影响了估计450万美国人，在美国人口中越来越常见。