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HDL Function in Human Disease

HDL 在人类疾病中的功能

基本信息

批准号：
10089335
负责人：
MACRAE F LINTON
金额：
$ 262.1万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10089335
关键词：
Acceleration Apoproteins Arterial Fatty Streak Arteries Atherosclerosis Bioinformatics Biometry Biostatistics Core Cardiovascular system Cell Death Cholesterol Chronic Chronic Kidney Failure Data Analyses Development Disease Endocytosis Ensure Environment Event Experimental Designs Familial Hypercholesterolemia Functional disorder Gene Expression Goals High Density Lipoproteins Human Impairment Inflammation Inflammatory Intestines Kidney Lesion Lipid Peroxidation Lipids Lipoproteins Low Density Lipoprotein oxidation Lymphatic Lysine Measurement MicroRNAs Modeling Modification Molecular Multiomic Data Mus Myocardial Infarction NAPE-PLD Necrosis Output Pathogenicity Phospholipids Plasma Proteins Research Residual state Resolution Rheumatoid Arthritis Risk Role Small RNA Stroke Structure TLR7 gene Testing Untranslated RNA adduct analog atherogenesis atheroprotective atherosclerosis risk cardiovascular risk factor chemical synthesis functional loss high density lipoprotein-3 human disease improved in vivo locked nucleic acid lymphatic dysfunction macrophage mesenteric lymphatics microbial microbiome novel novel therapeutic intervention particle programs receptor small molecule transcriptome sequencing

项目摘要

The central theme of our PPG is that HDL function is a critical determinant of atherogenesis and cardiovascular risk in chronic human disease. The goal of our research is to define the mechanisms for HDL functional loss in diseases associated with increased risk for atherosclerotic cardiovascular disease (ASCVD): Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of the PPG is that dysfunctional HDL contributes to the residual inflammatory risk of cardiovascular events. Reactive dicarbonyls including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids impairing HDL function. A major recent advance by our PPG is the discovery that two different small molecule dicarbonyl scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of changes in plasma lipid levels. The atherosclerotic lesions showed a dramatic decrease in necrosis and inflammation and had evidence for reduced efferocytosis. Projects 1 and 4 will both explore the hypothesis that reactive carbonyl- induced HDL dysfunction will impair macrophage efferocytosis. Project 1 will test the hypothesis that dicarbonyl scavengers promote remodeling of established atherosclerosis with resolution of inflammation. These studies will set the stage for a translational proof of concept study to test the hypothesis that the dicarbonyl scavenger 2-HOBA will inhibit modification of apoAI and HDL and improve HDL functions in humans with heterozygous FH and subjects with CAD without FH. Interestingly, we have recently discovered that lipoproteins are highly- enriched with small RNAs derived from bacterial and fungal species in the microbiome and environment (msRNA). Another major theme is that msRNA carried by HDL influence HDL function and atherogenesis. Project 2 will examine the hypothesis that CKD increases mesenteric lymphatic output and apoAI harboring harmful bioactive substances (IsoLG, miRNA, msRNA) that contribute to the increased risk of ASCVD. Importantly, microbial sRNAs are present in human and mouse atherosclerotic lesions. Project 3 will examine the hypothesis that HDL removes microbial sRNAs from lesion macrophages and suppresses pro-inflammatory gene expression through retro-endocytosis and msRNA acceptance. In addition, we will target macrophage TLR7/8 activation in vivo using non-targeting locked-nucleic acids (ntLNA) to inhibit atherosclerosis progression and promote regression. Project 4 will elucidate mechanisms whereby dicarbonyl modified lipoproteins potentiate inflammation and cell death in macrophages and determine if these alterations contribute to reduced efferocytosis. Overall, the proposed studies will advance our understanding of the role of HDL function in human disease and identify new therapeutic approaches for the treatment of ASCVD. There are 4 Cores: Core A. Administrative and Biostatistics; Core B Lipoprotein and HDL Function; Core C Chemical Synthesis and Lipid Peroxidation Analytical Core; and Core D Non-Coding RNA and Bioinformatics.

我们PPG的中心主题是HDL功能是动脉粥样硬化和心血管疾病的关键决定因素