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

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

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.