Licensing LncRNAs in Atherosclerosis

动脉粥样硬化中 LncRNA 的许可

基本信息

批准号：
10318206
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/10318206
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 Comb animal structure 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 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 Time Treatment Efficacy Untranslated RNA Work base burden of illness cardiogenesis cardiometabolism cardiovascular risk factor defined contribution dietary disease phenotype efficacy testing epigenomics 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 macrophage 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.

项目概要全球 1800 万心血管死亡中的大多数被认为是由于动脉粥样硬化造成的，也许是影响人类的最具破坏性的病理过程。最近新陈代谢猛增干扰将确保动脉粥样硬化不会消失。该应用程序解决了大量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链非编码 RNA (lncRNA) 影响动脉粥样硬化的发展心脏代谢异常。该提案的目标是 1) 定义 lncRNA 在心脏代谢疾病，2) 提高我们对 lncRNA 之间循环关系的理解保护和功能，3) 测试基于 lncRNA 的心血管治疗策略的功效疾病。与该应用程序的目标一致，我们的多中心协作小组在以下方面拥有集体专业知识： 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。该提案的总体假设是，可能存在是在脂质代谢中具有作用的lncRNA，其特征尚未确定，并且需要结合上下文进行靶向它们可以减轻相关模型中的疾病表型的特异性。使用综合筛选平台结合小鼠和人类研究，我们发现了参与肝脂质代谢的新型 lncRNA，开发了一种强大的管道，优先考虑 lncRNA 功能发现，并引入体内 lncRNA 的新工具扰动。目标 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针对病变的基于 lncRNA 的疗法。在目标 2 中，我们研究了 lncRNA 在肝细胞中的功能脂质代谢并测试尽管序列进化但跨物种功能保守的证据。这些研究有望为非编码基因调控的重要性提供基础见解。心脏代谢控制并为基于 lncRNA 的心血管疾病治疗提供框架。在总之，这一以发现为导向的提案将填补动脉粥样硬化领域的巨大知识空白和lncRNA生物学。