Long Non-coding RNAs in Cardiometabolic Disease

长非编码RNA在心脏代谢疾病中的作用

• 批准号: 9108166
• 负责人: Tamer Sallam
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108166
• 关键词: ATP binding cassette transporter 1; Adenovirus Vector; Affect; Affinity; Agonist; Animals; Atherosclerosis; Binding; Binding Proteins; Binding Sites; Biological; Biology; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cells; Cholesterol; Cholesterol Homeostasis; Chromatin; Comorbidity; Data; Development; Diagnostic; Disease; Excretory function; Exhibits; Feedback; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Health; High Fat Diet; Homeostasis; Lead; Link; Lipids; Lipoproteins; Liver; Liver X Receptor; Maintenance; Mammalian Cell; Mammals; Maps; Mediating; Mentors; Mentorship; Metabolic; Metabolism; MicroRNAs; Molecular; Mus; Names; National Heart, Lung, and Blood Institute; Nuclear; Oligonucleotides; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiological; Physiology; Play; Process; Proteins; RNA purification; Receptor Activation; Recruitment Activity; Regulation; Regulatory Element; Repression; Research Personnel; Research Project Grants; Response Elements; Role; SRE-2 binding protein; Scientist; Series; Serum; Signal Transduction; Sterols; Techniques; Technology; Testing; Therapeutic; Tissues; Training Programs; Transcriptional Regulation; Untranslated RNA; Work; Yang; Yin; absorption; atherogenesis; atheroprotective; base; cholesterol biosynthesis; defined contribution; drug development; fatty acid biosynthesis; frontier; human disease; improved; in vivo; insight; interest; lipid metabolism; liver function; loss of function; mimetics; next generation sequencing; novel; overexpression; programs; response; reverse cholesterol transport; skills; sterol homeostasis; therapeutic target; tool; uptake

 DESCRIPTION (provided by applicant): This proposal describes a five-year mentored physician-scientist training program to define the contribution of long non-coding RNAs in cardiovascular disease. Disturbances in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The liver X receptors (LXRs) is central regulators of sterol homeostasis. Activation of LXRs promotes reverse cholesterol transport/excretion and limits cholesterol uptake/absorption. The administration of LXR agonists has potent atheroprotective effects and reverses established disease; hence LXR agonists have generated strong interest as therapeutic targets. The actions of LXRs are opposed by Sterol Regulatory Element-binding Protein 2 (SREBP-2), the master regulator of cholesterol biosynthesis. Although prior studies have implicated microRNAs in lipoprotein metabolism, the contribution of other non-coding RNAs to lipid homeostasis and atherosclerosis remain unexplored. A unique group of non-coding RNAs known as large intergenic non-coding (linc) RNAs exhibit moderate evolutionary conservation and participate in diverse biologic processes with direct links to human diseases. Utilizing next-generation sequencing technology we identified a lincRNA that we named LeXis (Liver-expressed LXR-induced sequence) as a novel LXR target gene. The objective of this project is to define the function of LeXis in physiology and metabolism. My preliminary studies suggest that LeXis regulates serum cholesterol levels in vivo via feedback repression of SREBP-2 and cholesterol biosynthesis. I hypothesize that LeXis plays a role in cholesterol homeostasis through tissue-specific modulation of SREBP-2 transcription. I propose a series of molecular, cell biological, and animal studies to extend my preliminary observations and test my hypothesis. Targeting SREBP-2 in a context-specific manner may lower serum cholesterol while minimizing off target effects. Not only will our proposed work provide fundamental insights into how lncRNAs work, but may also open a new frontier for drug development, since it is conceivable that LeXis mimetic oligonucleotides might be used as therapeutic drugs. Thus, the proposed work is of high translational potential. The outlined program will allow the candidate to develop the skills and tools needed to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator. The aims of this project are aligned with the major strategic goal of NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.

 描述（由申请人提供）：该提案描述了一个为期五年的指导医生-科学家培训计划，以确定长链非编码RNA在心血管疾病中的作用。胆固醇稳态紊乱是心血管疾病和相关合并症的主要原因。肝脏X受体（LXRs）是固醇稳态的中心调节剂。LXR的活化促进胆固醇的逆向转运/排泄，并限制胆固醇的摄取/吸收。LXR激动剂的给药具有有效的动脉粥样硬化保护作用并逆转已建立的疾病;因此LXR激动剂作为治疗靶点产生了强烈的兴趣。LXR的作用受到固醇调节元件结合蛋白2（SREBP-2）的反对，SREBP-2是胆固醇生物合成的主要调节剂。虽然先前的研究已经暗示microRNA参与脂蛋白代谢，但其他非编码RNA对脂质稳态和动脉粥样硬化的贡献仍然未被探索。一组独特的非编码RNA被称为大基因间非编码（linc）RNA，表现出适度的进化保守性，并参与与人类疾病直接相关的多种生物学过程。利用下一代测序技术，我们鉴定了一种lincRNA，我们将其命名为LeXis（肝脏表达的LXR诱导序列）作为新型LXR靶基因。本项目的目的是确定LeXis在生理学中的功能， 新陈代谢.我的初步研究表明，LeXis通过反馈抑制SREBP-2和胆固醇生物合成来调节体内血清胆固醇水平。我推测LeXis通过组织特异性调节SREBP-2转录在胆固醇稳态中发挥作用。我提出了一系列的分子，细胞生物学和动物研究来扩展我的初步观察和测试我的假设。以特定背景的方式靶向SREBP-2可以降低血清胆固醇，同时最大限度地减少脱靶效应。我们提出的工作不仅将为lncRNA如何工作提供基本的见解，而且还可能为药物开发开辟新的前沿，因为可以想象LeXis模拟寡核苷酸可能被用作治疗药物。因此，所提出的工作具有很高的翻译潜力。概述的程序将允许候选人开发所需的技能和工具，开始这个研究项目，同时有必要的指导和支持，朝着成熟成为一个独立的调查员的目标。该项目的目标与NHLBI的主要战略目标一致，以提高我们对健康和疾病的分子和生理基础的理解。