Long Non-coding RNA as Mediators of Metabolic Disease

肥胖、糖尿病以及伴随的血脂和血压失调--统称为 “心脏代谢疾病”(CMD)--是心血管疾病的主要诱因。尽管有长期的数据 在CMD中暗示了小的非编码RNA，关于长的非编码RNA(LncRNAs)，人们知之甚少。 最近的动物研究表明，lncRNAs在脂质动态平衡、脂肪产热和 心肌重构，每一个都是CMD的关键。虽然动物研究可能会增加对lncRNA的怀疑 为了确定它们的作用，对人体组织的研究势在必行。研究集中在LncRNA的表达上。 人类CMD的中心组织对于理解CMD分子生理学的新方面至关重要 及其对心血管健康的下游影响。棕色脂肪组织(BAT)，能量集中 支出调节和新陈代谢与体重指数(BMI)呈负相关。初步数据 来自我们的小组使用来自蝙蝠和白色脂肪组织的人类脂肪细胞(WAT)已经识别出特定的 随着体重指数和糖尿病的增加，差异表达和比例改变的lncRNAs。目前， 在电子计算机测定中，对lncRNA-mRNA的调节仍然存在问题(由于缺乏精选资源)，以及 来自CMD高危人群和下游人群的可接触组织(例如血浆)的大规模验证 心血管风险是缺乏的。因此，必须(1)理解lncRNAs在人类中的作用 在与CMD相关的人体组织中表达；(2)确定lncRNA和mRNA表达之间的协调变化(AS LncRNA调控的可能靶点)；(3)包括lncRNA和cmd表型之间的关联研究 使未来在CMD中进行更大规模的机械研究成为可能。 在这里，我们假设lncRNAs在BAT和WAT中差异表达或在脂肪形成中相关 将(1)与CMD发病机制中心基因的表达相关，(2)在 作为已知影响CMD和心血管疾病的心脏代谢扰动的函数的血浆(例如， 减肥手术、胰岛素抵抗)。为了解决这一中心假设，我们汇集了我们的初步 人类脂肪组织RNA-SEQ数据和几个非常独特的来源：(1)正在进行的WAT、BAT和血浆 从NIH临床中心和我们机构的预期资源收集；(2)NIH资助的一项研究 我们进行了非编码RNA定量的减肥手术前后的个体 (U54HL112311)，并有初步数据证实lncRNAs随着体重的下降而发生较大变化；(3) 全人群数据(n=3100)，包括cmd、信使核糖核酸测量和可获得的lncRNA 分析。该应用基于提供候选LncRNA的初步数据，这些候选LncRNA 在新陈代谢活性脂肪中表达。它得到了积极的合作和之前收集的样本的支持 来自NIH/NHLBI赞助的研究，以及识别可能的LncRNA的创新生物信息学方法 基因靶标。所有数据都将向公众开放，并作为共享资源创建。

Obesity, diabetes, and accompanying lipid and blood pressure dysregulation—collectively termed “cardiometabolic disease” (CMD)—is a major contributor to cardiovascular disease. Despite long-standing data implicating small non-coding RNAs in CMD, less is known in regards to long non-coding RNAs (lncRNAs). Animal studies have recently suggested a role for lncRNAs in lipid homeostasis, fat thermogenesis and myocardial remodeling, each critical to CMD. While animal studies may heighten a suspicion for lncRNAs in CMD, studies in human tissue are imperative to establish their role. Studies focused on lncRNA expression in tissues central to CMD in humans are crucial to understand novel aspects of the molecular physiology of CMD and its downstream impact on cardiovascular health. Brown adipose tissue (BAT), central in energy expenditure regulation and metabolism, is inversely correlated with body-mass index (BMI). Preliminary data from our group using human adipocytes from BAT and white adipose tissue (WAT) has identified specific lncRNAs that are differentially expressed and altered in proportion with increasing BMI and diabetes. Currently, in silico determination of lncRNA-mRNA regulation remains problematic (due to lack of curated resources), and large-scale validation in accessible tissue (e.g., plasma) from populations at-risk for CMD and downstream cardiovascular risk is lacking. Therefore, understanding the role of lncRNAs in humans must (1) be performed in human tissues relevant to CMD; (2) identify coordinate changes between lncRNA and mRNA expression (as possible targets of lncRNA regulation); (3) include association studies between lncRNAs and CMD phenotypes to enable future larger mechanistic studies in CMD. Here, we hypothesize that lncRNAs differentially expressed in BAT vs. WAT or relevant in adipogenesis will be (1) associated with expression of genes central to CMD pathogenesis and (2) dynamically expressed in plasma as a function of cardiometabolic perturbations known to impact CMD and cardiovascular disease (e.g., bariatric surgery, insulin resistance). To address this central hypothesis, we bring together our preliminary human adipose tissue RNA-seq data with several very unique resources: (1) ongoing WAT, BAT, and plasma collection from prospective resources at the NIH Clinical Center and our institution; (2) an NIH-funded study of individuals pre-/post-bariatric surgery in which we have performed non-coding RNA quantification (U54HL112311) and have preliminary data establishing large changes in lncRNAs with weight loss; (3) population-wide data (n=3100) including CMD, mRNA measurements, and available RNA for lncRNA analyses. This application is based on preliminary data providing candidate lncRNAs that are differentially expressed in metabolically active fat. It is bolstered by active collaborations and samples previously collected from NIH/NHLBI sponsored studies, as well as innovative bioinformatics methods to identify possible lncRNA gene targets. All data will be made publically available and created as a shared resource.