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Impact of self-association on structure and function of apolipoprotein A-I

自缔合对载脂蛋白A-I结构和功能的影响

基本信息

批准号：
9024607
负责人：
Giorgio Cavigiolio
金额：
$ 40.5万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-17 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024607
关键词：
ATP-Binding Cassette Transporters Address Affect Alzheimer&apos s Disease Antiatherogenic Apolipoprotein A-I Apolipoproteins Apolipoproteins A Applications Grants Area Arterial Fatty Streak Arteries Atherosclerosis Binding Biological Assay Biological Models Biological Process Cardiovascular Diseases Cardiovascular system Cell Line Cell membrane Cells Cholesterol Data Developed Countries Development Diabetes Mellitus Disease Disease Progression Electron Microscopy Equilibrium Fluorescence Fluorescence Resonance Energy Transfer Formulation Functional disorder Goals High Density Lipoproteins High temperature of physical object Human In Vitro Incidence Individual Inflammation Knowledge Lead Lipid Binding Lipids Lipoproteins Measures Mediating Membrane Membrane Transport Proteins Modeling Molecular Sieve Chromatography Morphology Mutation Nature Pathogenesis Pathway interactions Physiological Plasma Predisposition Prevention Property Proteins Public Health Reaction Research Research Project Grants Rest Risk Assessment Role Secondary to Spectrum Analysis Stress Structure Techniques Testing Ursidae Family Variant amyloid fibril formation base biomarker evaluation cardiovascular disorder risk cardiovascular health cardiovascular risk factor design dimer gel electrophoresis glycation in vivo light scattering macrophage monomer mortality novel novel therapeutic intervention novel therapeutics oxidation protein function research clinical testing therapy development

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this grant proposal is to demonstrate that self-association of apolipoprotein A-I (apoA-I) is a functional feature of the protein and that alteration of its native state of self-association is involved in mechanisms leading to disease. Self-association is an inherent property of the lipid-free forms of several exchangeable apolipoproteins, including apoA-I, the main protein component of HDL and an established antiatherogenic factor. Monomeric lipid-free apoA-I is believed to be the biologically active species. But abnormal conditions, such as specific mutations or oxidation, produce an altered state of self-association that may contribute to apoA-I dysfunction. Although the functional role of self-association in some apolipoproteins has been established, the influence of self-association on apoA-I function has not been studied before because of technical limitations that are addressed and overcome in this project. Replacement of apoA-I's Trps with Phes (¿W-apoA-I) leads to unusually large and stable self-associated species. At least four self-associated species of ¿W-apoA-I can be isolated and will be used here as a model of self-association to analyze its role in determining apoA-I's structure, function, and susceptibility to mechanisms leading to dysfunction. The three overlapping areas to be investigated in this project are: 1. Define the effects of self-association at all levels of apoA-I structure, from secondary to quaternary. The nature of the inter-molecular interactions that are involved in apoA-I self-association will be established and the structural details underlying the loss of lipid-binding efficiency for increasing degrees of self- association will be determined. This structural knowledge will help to understand the mechanisms whereby alteration of the protein self-association state affects its biological function. 2. Characterize how the self-association state o lipid-free apoA-I affects its function as recipient of lipids released from cells in the biogenesisof HDL. The efficiency of different apoA-I self-associated species in activating lipid release mediated by different cell membrane transporters will be determined. Including ABCA1, which is the primary mechanism underlying the anti-atherogenic function of apoA-I. a. Demonstrate that the self-association state of lipid-free apoA-I modulate the protein susceptibility to mechanisms leading to dysfunction. The vulnerability of different self-associated species to reactions that are implicated in the pathogenesis of atherosclerosis and diabetes will be tested. The possible role of self-association in protecting apoA-I from conditions which promote amyloid fibril formation, a contributing mechanism to atherosclerosis progression, will be also evaluated. These studies are highly significant for public health because determining a new functional aspect of apoA- I, which is one of the most important known anti-atherogenic factors, bears potential for the formulation of new therapies and the development of new biomarkers for the evaluation of cardiovascular disease risk.