Long Non-coding RNAs in Cardiometabolic Disease

 描述(由申请人提供)：本提案描述了一项为期五年的有指导的医生-科学家培训计划，以确定长非编码RNA在心血管疾病中的作用。胆固醇平衡失调是心血管疾病和相关并存的主要因素。肝脏X受体(LXRs)是类固醇稳态的中枢调节因子。LXRs的激活促进了胆固醇的反向转运/排泄，限制了胆固醇的摄取/吸收。给予LXR激动剂有很强的动脉粥样硬化保护作用，可以逆转既往的疾病；因此，LXR激动剂作为治疗靶点引起了人们的浓厚兴趣。固醇调节元件结合蛋白2(SREBP-2)是胆固醇生物合成的主要调节因子，其作用受到LXRs的反对。尽管先前的研究表明microRNAs与脂蛋白代谢有关，但其他非编码RNAs对脂质稳态和动脉粥样硬化的作用仍未被探索。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过程。利用下一代测序技术，我们发现了一个新的LXR靶基因，我们将其命名为Lexis(肝脏表达的LXR诱导序列)。本项目的目标是确定词汇在生理学和生理学中的功能 新陈代谢。我的初步研究表明，Lexis通过反馈抑制SREBP-2和胆固醇的生物合成来调节体内的血清胆固醇水平。我推测，Lexis通过对SREBP-2转录的组织特异性调节，在胆固醇稳态中发挥作用。我提出了一系列分子、细胞生物学和动物研究来扩展我的初步观察并检验我的假设。以特定上下文的方式靶向SREBP-2可能会降低血清胆固醇，同时将偏离目标的影响降至最低。我们拟议的工作不仅将为lncRNA如何发挥作用提供基本的见解，而且还可能为药物开发开辟一个新的前沿，因为可以想象Lexis模拟寡核苷酸可能被用作治疗药物。因此，拟议的工作具有很高的翻译潜力。概述的计划将允许候选人发展开展这一研究项目所需的技能和工具，同时拥有必要的指导和支持，以实现成熟为独立调查人员的目标。该项目的目标与NHLBI的主要战略目标保持一致，以提高我们对健康和疾病的分子和生理学基础的理解。

 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.