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.

描述（由适用提供）：动脉粥样硬化是心脏病发作和中风的根本原因，是全球死亡和痛苦的主要原因。清道夫受体BI（SR-BI）通过用作HDL胆固醇的肝受体，调节巨噬细胞胆固醇稳态和动脉斑块中的存活，在预防动脉粥样硬化中起着至关重要的作用。最近的研究通过预防凋亡实施了细胞存活中的SR-BI。有趣的是，我们的初步研究暗示了SR-BI在调节中的关键作用自噬，这是促进细胞存活的另一种关键机制。此外，我们的数据表明，通过调节血管生成蛋白，SR-BI在介导细胞存活中的新作用是一种RNase III酶，该酶介导TRNA裂解以产生tRNA衍生的SMRNA（TDRS），通过蛋白质翻译抑制和转录后的mRNA靶标的促进细胞存活。重要的是，我们最近发现TDR代表了HDL上最富有的SMRNA类，因为在参考基因组中，超过60％的SMRNA与TRNA基因座对齐。令人惊讶的是，我们的初步研究表明，与健康的主动脉相比，动脉粥样硬化血管的TDR水平增加。在特定的目标1中，我们将检查以下假设，即SR-BI通过控制作者助剂助焊剂来限制巨噬细胞死亡和泡沫细胞的形成来拮抗动脉粥样硬化。在特定的目标2中，我们将研究以下假设：巨噬细胞SR-BI通过调节血管葡萄蛋白活性通过特定的TDR表达促进细胞存活。在特定的目标3中，我们将定义HDL-TDR通信对动脉粥样硬化的SR-BI调节的影响。此外，我们将研究SR-BI缺乏对TDR的签名对HDL的签名的影响，该人具有scarb1基因的常见和罕见功能变化的人类。此外，我们将研究这些人类Scarb1功能损失变体对巨噬细胞自噬的影响。更好地理解哪些过程导致巨噬细胞将TDR导出到HDL以及这如何促进动脉粥样硬化可能会导致发现动脉粥样硬化的新机制和新型药物靶标的鉴定。我们的最终目标是利用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，以在预防和治疗血脂异常和动脉粥样硬化的预防和治疗方面获得治疗性增长。