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

 描述(申请人提供)：动脉粥样硬化，心脏病发作和中风的根本原因，是世界范围内死亡和痛苦的主要原因。清道夫受体BI(SR-BI)作为高密度脂蛋白的肝脏受体，通过调节巨噬细胞胆固醇的稳态和动脉斑块的存活，在预防动脉粥样硬化中发挥重要作用。最近的研究表明，SR-BI通过阻止细胞凋亡而参与细胞存活。有趣的是，我们的初步研究表明SR-BI在调节 自噬是促进细胞存活的另一种关键机制。此外，我们的数据表明，SR-BI通过调节血管生成素在调节细胞存活方面发挥了新的作用，血管生成素是一种RNase III酶，它介导tRNA裂解产生tRNA衍生的smRNAs(TDRs)，通过抑制蛋白质翻译和转录后抑制mRNA靶标来促进细胞存活。重要的是，我们最近发现TDR代表了在高密度脂蛋白上最丰富的一类smRNAs，因为超过60%的smRNAs与参考基因组中的tRNA位点比对。值得注意的是，我们的初步研究表明，与健康的大动脉相比，动脉粥样硬化的血管中的TDRS水平升高。在特定的目标1中，我们将检验SR-BI通过控制自噬流量来限制巨噬细胞死亡和泡沫细胞形成来对抗动脉粥样硬化的假设。在特定的目标2中，我们将检验巨噬细胞SR-BI通过调节血管生成素活性而通过特定的TDR表达促进细胞存活的假设。在具体目标3中，我们将明确SR-BI调节高密度脂蛋白-胸腺嘧啶核苷在动脉粥样硬化中的作用。此外，我们将研究SR-BI缺乏对具有SCARB1基因常见和罕见功能丧失变种的人的TDRS在高密度脂蛋白上的签名的影响。此外，我们还将研究这些人类SCARB1功能缺失变异对巨噬细胞自噬的影响。更好地了解是什么过程导致巨噬细胞将TDR输出到高密度脂蛋白，以及这如何促进动脉粥样硬化的形成，可能会导致发现动脉粥样硬化的新机制，并识别新的药物靶点。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，在预防和治疗血脂异常和动脉粥样硬化方面获得治疗收益。

 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.