Long Non-coding RNA as Mediators of Metabolic Disease

长非编码 RNA 作为代谢疾病的介质

• 批准号: 10496586
• 负责人: JANE E Freedman
• 金额: $ 21.76万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10496586
• 关键词: Long; Non; coding; RNA; Mediators

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.

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原因。尽管有长期的数据 在CMD中涉及小的非编码RNA，关于长的非编码RNA（lncRNA）知之甚少。 最近的动物研究表明，lncRNA在脂质稳态、脂肪产热和代谢中的作用。 心肌重塑，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， CMD，在人体组织中的研究是必要的，以确定其作用。研究集中在lncRNA表达， 人类CMD的核心组织对于了解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），能量中心 支出调节和代谢，与体重指数（BMI）呈负相关。初步数据 我们的研究小组使用来自BAT和白色脂肪组织（WAT）的人脂肪细胞， lncRNA的差异表达和改变的比例增加BMI和糖尿病。目前， lncRNA-mRNA调控的计算机测定仍然存在问题（由于缺乏策划资源）， 在可接近组织中的大规模验证（例如，血浆）， 缺乏心血管风险。因此，了解lncRNA在人类中的作用必须（1）进行 在与CMD相关的人体组织中;（2）鉴定lncRNA和mRNA表达之间的协调变化（如 lncRNA调节的可能靶点）;（3）包括lncRNA与CMD表型之间的关联研究 以使未来更大的机制研究在CMD。 在此，我们假设在BAT与WAT中差异表达的lncRNA或与脂肪形成相关， 将（1）与CMD发病机制的核心基因的表达相关，和（2）在 血浆作为已知影响CMD和心血管疾病的心脏代谢紊乱的函数（例如， 减肥手术、胰岛素抵抗）。为了解决这一核心假设，我们将我们的初步假设 人类脂肪组织RNA-seq数据与几个非常独特的资源：（1）正在进行的WAT，BAT，和血浆 从NIH临床中心和我们机构的前瞻性资源收集;（2）NIH资助的一项研究， 个体减肥手术前/后，我们进行了非编码RNA定量 （U 54 HL 112311），并具有初步数据，建立了体重减轻时lncRNA的大变化;（3） 全人群数据（n=3100），包括CMD、mRNA测量和lncRNA的可用RNA 分析。本申请是基于提供候选lncRNA的初步数据，所述候选lncRNA在细胞内差异表达。 在代谢活性脂肪中表达。它得到了积极合作和以前收集的样本的支持 以及创新的生物信息学方法来识别可能的lncRNA 基因靶点所有数据都将作为共享资源提供并创建。