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:
- 金额:$ 10.26万
- 依托单位:
- 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:
- 关键词:AccountingAortaApolipoprotein EApoptosisApoptoticArterial Fatty StreakArteriesAtherosclerosisAutophagocytosisAutophagosomeBiological PreservationCardiovascular DiseasesCardiovascular systemCause of DeathCell CommunicationCell SurvivalCellsCellular translocationCessation of lifeChemicalsCholesterolCholesterol EstersCholesterol HomeostasisCommunicationComputer SimulationDataDevelopmentDrug TargetingDyslipidemiasEndothelial CellsEnzymesExtracellular FluidExtramural ActivitiesFoam CellsGene Expression RegulationGenerationsGenesGoalsHealthHepaticHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHomeostasisHumanIn VitroInflammationLeadMediatingMediator of activation proteinMessenger RNAMicroRNAsMolecularMusMyocardial InfarctionNational Heart, Lung, and Blood InstituteNucleic AcidsPathway interactionsPlayPreventionProcessProtein BiosynthesisProteinsRegulationReportingResolutionRibonuclease IIIRoleSR-BI receptorScienceSmall RNASocietiesStressStrokeTestingTherapeuticTransfer RNATranslationsUntranslated RNAVariantWorkangiogeninatherogenesisbasegene repressionin vivointercellular communicationloss of functionmacrophagemacrophage scavenger receptorsnew therapeutic targetnovelnovel strategiespreventprogramspublic health relevancereceptorreference genomeresponsetraffickingtranslational approachuptake
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,是全球死亡和痛苦的主要原因。清道夫受体BI(SR-BI)通过充当HDL胆固醇的肝受体和通过调节巨噬细胞胆固醇稳态和在动脉斑块中的存活在预防动脉粥样硬化中起关键作用。最近的研究表明,SR-BI通过防止细胞凋亡而参与细胞存活。有趣的是,我们的初步研究暗示了SR-BI在调节
自噬,另一个促进细胞存活的关键机制。此外,我们的数据表明SR-BI在通过调节血管生成素介导细胞存活中的新作用,血管生成素是一种介导tRNA切割以产生tRNA衍生的smRNAs(tDR)的RNase III酶,其通过蛋白质翻译抑制和mRNA靶的转录后抑制促进细胞存活。重要的是,我们最近发现tDR代表HDL上最丰富的一类smRNAs,因为超过60%的smRNAs与参考基因组中的tRNA基因座对齐。引人注目的是,我们的初步研究表明,动脉粥样硬化血管与健康的动脉粥样硬化血管相比,tDR水平增加。在具体目标1中,我们将检验SR-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而拮抗动脉粥样硬化形成的假设。在特定目标2中,我们将研究巨噬细胞SR-BI通过调节血管生成素活性通过特异性TDR表达促进细胞存活的假设。在具体目标3中,我们将定义SR-BI调节HDL-tDR通讯在动脉粥样硬化中的影响。此外,我们将研究SR-BI缺陷对人类常见和罕见SCARB 1基因功能丧失变体的HDL上tDR签名的影响。此外,我们将研究这些人SCARB 1功能丧失变体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HDL以及这如何有助于动脉粥样硬化形成,将可能导致发现动脉粥样硬化的新机制和鉴定新的药物靶点。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中获得治疗效果。
项目成果
期刊论文数量(0)
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{{ truncateString('MACRAE F LINTON', 18)}}的其他基金
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
- 批准号:
9195133 - 财政年份:2016
- 资助金额:
$ 10.26万 - 项目类别:
Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH
二羰基清除剂可改善 FH 中的 HDL 功能并减少动脉粥样硬化
- 批准号:
10327715 - 财政年份:2014
- 资助金额:
$ 10.26万 - 项目类别:
Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH
二羰基清除剂可改善 FH 中的 HDL 功能并减少动脉粥样硬化
- 批准号:
10089340 - 财政年份:2014
- 资助金额:
$ 10.26万 - 项目类别:
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