Licensing LncRNAs in Atherosclerosis

动脉粥样硬化中 LncRNA 的许可

基本信息

批准号：
10533322
负责人：
Tamer Sallam
金额：
$ 62.7万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533322
关键词：
ATP binding cassette transporter 1 Address Affect Affinity Animals Atherosclerosis Binding Binding Sites Biological Biological Assay Biology Bone Marrow Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cells Cessation of life Cholesterol Chromatin Coronary Arteriosclerosis Cues Data Development Diagnostic Diet Ensure Evolution Foam Cells Gene Expression Gene Expression Regulation Genes Genetic Goals Heart Diseases Hepatic Homeostasis Human Immune signaling Inflammation Junk DNA Knock-out Knowledge Lesion Licensing Link Lipids Liver Macrophage Manuscripts Metabolic Metabolic Diseases Metabolism Methodology Modeling Molecular Morbidity - disease rate Mus Pathologic Processes Pathway interactions Phenotype Physiological Plasma Play Recurrence Regulation Reporting Role Series Specificity Sterols Testing Therapeutic Treatment Efficacy Untranslated RNA Work burden of illness cardiometabolism cardiovascular risk factor defined contribution dietary disease phenotype efficacy testing epigenomic profiling fatty liver disease gain of function gene therapy genome wide association study genome-wide heart disease risk human disease improved in vivo in vivo evaluation innovation insight lipid metabolism loss of function mortality mouse model nonalcoholic steatohepatitis novel pleiotropism preference reverse cholesterol transport screening therapeutic RNA therapeutic target tool trait treatment strategy

项目摘要

PROJECT SUMMARY The majority of the 18 million worldwide cardiovascular deaths are thought to be due to atherosclerosis, perhaps the single most devastating pathologic process affecting mankind. The recent surge in metabolic disturbances will ensure that atherosclerosis will not just fade away. This application addresses substantial knowledge gaps and capitalizes on recent discoveries from our group and new preliminary evidence suggesting that long noncoding RNAs (lncRNAs) influence the development of atherosclerosis and cardiometabolic abnormalities. The objective of this proposal is to 1) define the contributions of lncRNAs in cardiometabolic diseases, 2) improve our understanding of recurrent relationships between lncRNA conservation and function and 3) test the efficacy of lncRNA-based therapeutic strategies in cardiovascular disease. Aligned with goals of this application our multicenter collaborative group has collective expertise in lncRNA biology, atherosclerosis and metabolic disease, epigenomic profiling methodologies, and dissecting gene-phenotype relationships in human disease. The overarching hypothesis of this proposal is that there may be lncRNAs with roles in lipid metabolism that are yet to be characterized and when targeted with context specificity they can mitigate disease phenotypes in relevant models. Using an integrative screening platform combing mouse and human studies, we identify novel lncRNA involved in hepatic lipid metabolism, develop a robust pipeline that prioritizes lncRNA functional discovery, and introduce new tools for lncRNA in vivo perturbations. Aim 1, will determine role of macrophage lncRNAs in atherosclerosis and explore opportunities for lncRNA-based therapeutics targeting lesions. In Aim 2, we investigate the function of lncRNAs in hepatic lipid metabolism and test for evidence of cross-species functional conservation despite sequence evolution. These studies are expected to shed fundamental insight into the significance of noncoding gene regulation in cardiometabolic control and provide a framework for lncRNA-based therapeutics in cardiovascular disease. In summary, this discovery-oriented proposal will fill substantial knowledge gaps in the fields of atherosclerosis and lncRNA biology.

项目摘要全球1800万个心血管死亡中的大多数被认为是由于动脉粥样硬化而造成的也许是影响人类的最毁灭性的病理性过程。最近的代谢激增干扰将确保动脉粥样硬化不仅会消失。该申请可实现知识差距并利用我们小组的最新发现和新的初步证据表明长的非编码RNA（LNCRNA）会影响动脉粥样硬化和心脏代谢异常。该提议的目的是1）定义lncrnas在心脏代谢性疾病，2）提高我们对lncRNA之间复发关系的理解保护和功能以及3）测试基于LNCRNA的治疗策略在心血管中的功效疾病。与此应用程序的目标保持一致，我们的多中心协作小组具有集体专业知识 LNCRNA生物学，动脉粥样硬化和代谢疾病，表观基因组分析方法和解剖人类疾病中的基因 - 表型关系。该提议的总体假设是在脂质代谢中扮演角色的lncRNA，尚待表征，并以上下文为目标特异性可以减轻相关模型中的疾病表型。使用集成筛选平台梳理小鼠和人类研究，我们确定了与肝脂质代谢有关的新型lncRNA，发展优先级lncrna功能发现的强大管道，并引入了lncrna in Vivo的新工具扰动。 AIM 1，将确定巨噬细胞LNCRNA在动脉粥样硬化中的作用并探索机会用于基于LNCRNA的靶向病变的治疗剂。在AIM 2中，我们研究了LNCRNA在肝中的功能脂质代谢并测试尽管序列进化，但跨物种功能保护的证据。预计这些研究将使对非编码基因调节在非编码基因的重要性的基本见解。心脏代谢控制并为心血管疾病中的基于LNCRNA的疗法提供框架。在总而言之，这个面向发现的建议将填补动脉粥样硬化领域的大量知识差距和lncrna生物学。