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：
9029105
负责人：
MACRAE F LINTON
金额：
$ 10.26万
依托单位：
VANDERBILT UNIVERSITY
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029105
关键词：
Accounting Aorta Apolipoprotein E Apoptosis Apoptotic Arterial Fatty Streak Arteries Atherosclerosis Autophagocytosis Autophagosome Biological Preservation Cardiovascular Diseases Cardiovascular system Cause of Death Cell Communication Cell Survival Cells Cellular translocation 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 Health Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human In Vitro Inflammation Lead Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Mus Myocardial Infarction National Heart, Lung, and Blood Institute Nucleic Acids Pathway interactions Play Prevention 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.

描述（由申请人提供）：动脉粥样硬化是心脏病发作和中风的根本原因，是全世界死亡和痛苦的主要原因。清道夫受体 BI (SR-BI) 通过充当肝受体，在预防动脉粥样硬化方面发挥着至关重要的作用。最近的研究表明 SR-BI 通过防止细胞凋亡来影响细胞存活。表明 SR-BI 在调节中发挥着关键作用自噬是促进细胞存活的另一个关键机制。此外，我们的数据表明 SR-BI 通过调节血管生成素在介导细胞存活中发挥新作用，血管生成素是一种 RNase III 酶，可介导 tRNA 裂解以产生 tRNA 衍生的 smRNA (tDR)。它通过蛋白质翻译抑制和 mRNA 靶标的转录后抑制来促进细胞存活。重要的是，我们最近发现 tDR 代表了 smRNA 中最丰富的类别。 HDL，因为超过 60% 的 smRNA 与参考基因组中的 tRNA 位点对齐，我们的初步研究表明，与健康主动脉相比，动脉粥样硬化血管的 tDR 水平增加，我们将检验 SR- 的假设。 BI 通过控制自噬通量来限制巨噬细胞死亡和泡沫细胞形成，从而对抗动脉粥样硬化形成。在具体目标 2 中，我们将检验以下假设：巨噬细胞 SR-BI 通过调节血管生成素活性来促进细胞存活，在具体目标 3 中，我们将定义 SR-BI 对 HDL-tDR 通讯的调节对动脉粥样硬化的影响。具有常见和罕见 SCARB1 基因功能丧失变异的人类的 HDL tDR 特征存在 BI 缺陷此外，我们将研究这些人类的影响。更好地了解巨噬细胞自噬过程中的 SCARB1 功能缺失及其如何导致动脉粥样硬化，可能有助于发现动脉粥样硬化的新机制并确定新的药物靶点。最终目标是利用 SR-BI 在调节自噬、血管生成素和 tRNA 衍生的小 RNA 中的这些新作用，在预防和治疗血脂异常和动脉粥样硬化。