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Long Non-coding RNAs in the Regulation of Adipogenesis and Obesity

长非编码 RNA 在脂肪生成和肥胖调节中的作用

基本信息

批准号：
10394951
负责人：
Tamer Sallam
金额：
$ 38.08万
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：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394951
关键词：
ATAC-seq Acute Adenovirus Vector Adipocytes Adipose tissue Affect Affinity Animal Model Animals Architecture Binding Binding Proteins Binding Sites Biological Biological Assay Biological Process Cardiometabolic Disease Cardiovascular Diseases Catalogs Cause of Death Cell Nucleus Cells Cholesterol Cholesterol Homeostasis Chromatin Chromosomes Chronic Cues DNA-Binding Proteins Data Development Diabetes Mellitus Diagnostic Disease Dyslipidemias Ensure Event Failure Fatty acid glycerol esters Gene Expression Genes Genetic Transcription Genomics High Fat Diet Homeostasis Human Impairment Individual Link Lipids Liver Liver X Receptor Location Mammalian Cell Maps Mediator of activation protein Metabolic Metabolic Control Metabolic Diseases Metabolism Molecular Mus Nucleosomes Nucleotides Obesity PPAR gamma Pathway interactions Pattern Physiological Play Public Health Regulation Regulatory Element Resistance Resolution Response Elements Role SRE-2 binding protein Series Signal Transduction Sterols Testing Therapeutic Tissues Transcription Coactivator Transcription Repressor Transcriptional Regulation Untranslated RNA Woman Work Yang Yin atherogenesis cardiovascular risk factor cholesterol biosynthesis comorbidity defined contribution diet-induced obesity dietary drug development energy balance fatty acid biosynthesis frontier insight knock-down lipid biosynthesis loss of function men novel novel diagnostics novel therapeutic intervention promoter response risk mitigation sterol homeostasis trait transcription factor uptake

项目摘要

PROJECT SUMMARY Metabolic disturbances such as dyslipidemia, diabetes and obesity are associated with a number of comorbid conditions including devastating forms of cardiovascular disease. Recently, the discovery of an attractive group of molecules known as long noncoding RNAs (lncRNAs) has introduced a new “catalog” of diagnostic and therapeutic opportunities for cardiovascular risk mitigation. LncRNAs participate in diverse biologic processes but their involvement to cardiometabolic disease is less well explored. The objective of this project is to define the contributions and mechanisms of action of lncRNAs in adipose tissue formation and function. Capitalizing on our recent discovery of lncRNAs acting as responders to dietary cues and modulators of physiologic pathways with links to common diseases, we hypothesize that transcriptional regulation by long non-coding RNAs in white adipocyte tissue is essential for normal adipose tissue development. Reinforcing this premise our studies show that loss of the lncRNA LeXis is associated with failure to suppress de novo cholesterogenesis in adipocyte precursors and resistance to diet induced obesity. In aim1, we use a series of molecular, cell biological, and novel animal models to extend our preliminary observations and test out hypothesis defining the function of lncRNAs in adipose tissue. In aim2, we leverage recent technical advances interrogating the interplay between transcription factors and chromatin to investigate new mechanisms involved in metabolic control and spatial activation patterns of master adipogenic transcription factors. Our studies are expected to shed fundamental insights into mechanisms orchestrating adiposity and may offer new frontiers for drug development targeting obesity and metabolic traits.

项目摘要代谢紊乱如血脂异常、糖尿病和肥胖症与许多疾病相关。合并症，包括毁灭性的心血管疾病。最近，一组被称为长链非编码RNA（lncRNA）的有吸引力的分子引入了一种新的心血管风险缓解的诊断和治疗机会的“目录”。lncRNAs 参与多种生物学过程，但与心脏代谢疾病的关系不太好探讨了该项目的目标是确定联合国系统的贡献和行动机制， lncRNA在脂肪组织形成和功能中的作用利用我们最近发现的lncRNAs 作为饮食线索的反应者和生理途径的调节剂，我们假设白色脂肪细胞中长链非编码RNA的转录调控组织是正常脂肪组织发育所必需的。我们的研究表明， lncRNA LeXis的丢失与不能抑制新生胆固醇生成有关，脂肪细胞前体和抵抗饮食诱导的肥胖。在aim1中，我们使用一系列分子，细胞生物学和新的动物模型来扩展我们的初步观察和测试，定义lncRNA在脂肪组织中的功能的假说。在aim2中，我们利用最新的技术研究转录因子和染色质之间的相互作用，代谢控制和空间激活模式的主要脂肪形成机制转录因子我们的研究有望揭示协调肥胖，并可能为针对肥胖的药物开发提供新的前沿，代谢特征