Macrophage SR-BI Regulates Autophagy, Angiogenin and tRNA-derived small RNAs

巨噬细胞 SR-BI 调节自噬、血管生成素和 tRNA 衍生的小 RNA

基本信息

批准号：
9195133
负责人：
MACRAE F LINTON
金额：
$ 53.3万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195133
关键词：
Aorta Apolipoprotein E Apoptosis Apoptotic Arterial Fatty Streak Arteries Atherosclerosis Autophagocytosis Autophagosome Biological Preservation Blood Cardiovascular Diseases Cardiovascular system Cause of Death Cell Communication Cell Survival Cells Cessation of life Chemicals Cholesterol Cholesterol Esters Cholesterol Homeostasis Communication Computer Simulation Data Development Drug Targeting Dyslipidemias Endothelial Cells Enzymes Extracellular Fluid Extramural Activities Foam Cells Gene Expression Regulation Generations Genes Goals HDL receptor Health Heart Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human In Vitro Inflammation Institutes Lead Lung Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Mus Myocardial Infarction Nucleic Acids Pancreatic ribonuclease Pathway interactions Play Prevention Prevention approach Process Protein Biosynthesis Proteins Regulation Reporting Resolution Ribonuclease III Role SR-BI receptor Science Small RNA Societies Stress Stroke Testing Therapeutic Transfer RNA Translations Untranslated RNA Variant Work angiogenin atherogenesis base gene repression in vivo intercellular communication loss of function macrophage macrophage scavenger receptors new therapeutic target novel novel strategies prevent programs public health relevance receptor reference genome response trafficking translational approach uptake

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis, the underlying cause of heart attack and stroke, is a major cause of death and suffering worldwide. The scavenger receptor BI (SR-BI) plays crucial roles in preventing atherosclerosis both by serving as a hepatic receptor for HDL cholesterol and by regulating macrophage cellular cholesterol homeostasis and survival in the arterial plaque. Recent studies have implicated SR-BI in cell survival by preventing apoptosis. Interestingly, our preliminary studies implicate a critical role for SR-BI in regulating autophagy, another key mechanism for promoting cell survival. Furthermore, our data suggest a novel role for SR-BI in mediating cell survival through the regulation of angiogenin, a RNase III enzyme that mediates tRNA cleavage to produce tRNA-derived smRNAs (tDRs), which promote cell survival through protein translation suppression and post- transcriptional repression of mRNA targets. Importantly, we have recently found that tDRs represent the most abundant class of smRNAs on HDL, as over 60% of smRNAs were aligned to tRNA loci in the reference genomes. Strikingly, our preliminary studies suggest that atherosclerotic vessels have increased levels of tDRs compared to healthy aortas. In Specific Aim 1, we will examine the hypothesis that SR-BI antagonizes atherogenesis by controlling authophagic flux to limit macrophage death and foam cell formation. In Specific Aim 2, we will examine the hypothesis that macrophage SR-BI promotes cell survival by specific tDR expression through regulation of angiogenin activity. In Specific Aim 3, we will define the impact of SR-BI regulation of HDL-tDR communication in atherosclerosis. Furthermore, we will examine the impact of SR-BI deficiency on the signature of tDRs on HDL from humans with both common and rare loss-of function-variants of the SCARB1 gene. In addition, we will examine the impact of these human SCARB1 loss-of function variants on autophagy in macrophages. A better understanding of what processes lead macrophages to export tDRs to HDL and how this contributes to atherogenesis will likely lead to the discovery of new mechanisms underlying atherosclerosis and the identification of novel drug targets. Our ultimate goal is to leverage these novel roles of SR-BI in regulating autophagy, angiogenin and tRNA-derived small RNAs for therapeutic gain in the prevention and treatment of dyslipidemia and atherosclerosis.