Long Non-coding RNAs in Cardiometabolic Disease

长非编码RNA在心脏代谢疾病中的作用

基本信息

批准号：
8949599
负责人：
Tamer Sallam
金额：
$ 14.45万
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：
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/8949599
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 Diet Disease Excretory function Exhibits Fatty acid glycerol esters Feedback Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Goals Health Homeostasis Lead Link Lipids Lipoproteins Liver 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 receptor response reverse cholesterol transport skills sterol homeostasis therapeutic target tool uptake

项目摘要

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（由适用提供）：该提案描述了一项为期五年的物理科学家培训计划，以定义长期非编码RNA在心血管疾病中的贡献。胆固醇稳态的障碍是心血管疾病和相关合并症的主要因素。肝X受体（LXR）是固醇稳态的中心调节剂。 LXR的激活促进反向胆固醇的转运/排泄，并限制胆固醇的摄取/吸收。 LXR激动剂的给药具有潜在的动脉保护作用，并逆转已建立的疾病。因此，LXR激动剂已经引起了作为治疗靶标的浓厚兴趣。 LXR的作用与固醇调节元素结合蛋白2（SREBP-2）的作用是胆固醇生物合成的主要调节剂。尽管先前的研究已经在脂蛋白代谢中实施了microRNA，但其他非编码RNA对脂质稳态和动脉粥样硬化的贡献仍然出乎意料。一组独特的非编码RNA，称为大型基因间非编码（LINC）RNA暴露了现代进化保护，并参与了潜水员生物学过程，并与人类疾病有直接联系。利用下一代测序技术，我们确定了一个名为Lexis（肝脏表达LXR诱导的序列）为新的LXR靶基因的Lincrna。该项目的目的是定义Lexis在生理学和代谢。我的初步研究表明，Lexis通过SREBP-2和胆固醇生物合成的反馈表达来调节体内血清胆固醇水平。我假设Lexis通过SREBP-2转录的组织特异性调节在胆固醇稳态中起作用。我提出了一系列分子，细胞生物学和动物研究，以扩展我的初步观察并检验我的假设。以特定于上下文的方式靶向SREBP-2可以降低血清胆固醇，同时最大程度地减少靶向影响。我们提出的工作不仅会提供有关LNCRNA如何工作的基本见解，而且还可以为药物开发开辟新的领域，因为可以想象Lexis Mimimity寡核苷酸可以用作治疗药物。这是拟议的工作具有很高的翻译潜力。概述的计划将使候选人能够开发启动该研究项目所需的技能和工具，同时为了将目标和支持提供必要的心态和支持。该项目的目的与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基础的理解。