Functional Analysis of ACAT

ACAT的功能分析

基本信息

批准号：
7424002
负责人：
Ta Yuan CHANG
金额：
$ 37.28万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7424002
关键词：
7,7-azocholestanol Abbreviations Acyl Coenzyme A Acyltransferase Affect Alzheimer disease prevention Alzheimer&apos 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 Condition 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 Radioimmunoassay 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

项目摘要

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（由申请人提供）：酰基辅酶轴胆固醇酰基转移酶（ACAT）是存在于多种组织和细胞中的膜结合酶。 ACAT 使用长链脂肪酰辅酶 A 和胆固醇作为底物，催化胆固醇酯的生物合成，胆固醇酯是包装在极低密度脂蛋白和乳糜微粒核心中的部分中性脂质货物。在病理生理条件下，在负载胆固醇的巨噬细胞中，ACAT 将过量的胆固醇转化为胆固醇酯。这种作用减少了可流出的胆固醇量，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，它们编码两种相似但不同的蛋白质：ACAT1 和 ACAT2。这两种酶都是针对动脉粥样硬化和高脂血症等疾病的药物干预的潜在药物靶点。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。这项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。对于当前的提案，有两个具体目标。第一个目标是测试生化模型的某些关键特征，该模型旨在将 ACAT1 解释为变构酶。第二个目的是确定 ACAT 在 AD 小鼠模型中的病理生理学作用。第一个具体目标的成果将为ACAT提供第一个生化模型；该模型将有助于加深我们对 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学作用。该项目旨在建立 ACAT1 的生化模型，ACAT1 是一种对胆固醇代谢、运输和储存至关重要的酶。了解 ACAT 的行为方式和被抑制的情况，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病因和预防的了解，阿尔茨海默病是一种进行性脑部疾病，影响估计 4.5数百万美国人，并且在美国人口中变得越来越普遍。