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: 10083222
• 负责人: JANE E Freedman
• 金额: $ 20.17万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083222
• 关键词: Address; Adipocytes; Adipose tissue; Animals; Bariatrics; Bioinformatics; Biological; Blood Circulation; Blood Pressure; Body Weight decreased; Body mass index; Brown Fat; Cardiometabolic Disease; Cardiovascular Diseases; Cell Culture Techniques; Cell Respiration; Code; Cohort Studies; Collaborations; Collection; Communities; Data; Diabetes Mellitus; Diagnostic; Energy Metabolism; Fatty acid glycerol esters; Framingham Heart Study; Funding; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Heart failure; Homeostasis; Human; Individual; Institution; Insulin Resistance; Intervention; Investigation; Link; Lipids; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Target; National Heart, Lung, and Blood Institute; Norepinephrine; Nucleotides; Obesity; Outcome; Pathogenesis; Pathway interactions; Physiology; Plasma; Population; Populations at Risk; Proteins; RNA; RNA analysis; Regulation; Research; Resolution; Resource Sharing; Resources; Risk; Role; Sampling; Supraclavicular; Therapeutic; Thermogenesis; Time; Tissue Banks; Tissues; Transcriptional Regulation; Translations; United States National Institutes of Health; Untranslated RNA; Validation; Ventricular Remodeling; Visceral fat; bariatric surgery; base; biological systems; cardiometabolism; cardiovascular health; cardiovascular risk factor; clinical center; coronary artery calcification; cost efficient; differential expression; disease phenotype; epigenetic regulation; extracellular; human tissue; in silico; in vivo; innovation; insight; lipid biosynthesis; mRNA Expression; man; novel; obesity treatment; population based; primary outcome; programs; prospective; public health relevance; secondary outcome; targeted biomarker; transcriptome sequencing

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。尽管长期存在的数据 尽管小非编码RNA与CMD有关，但人们对长非编码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 心肌重塑，每一个都对 CMD 至关重要。虽然动物研究可能会增加人们对 lncRNA 的怀疑 CMD，对人体组织的研究必须确定它们的作用。研究重点是 lncRNA 表达 人类 CMD 的核心组织对于理解 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)，能量核心 支出调节和新陈代谢，与体重指数（BMI）呈负相关。初步数据 我们小组使用来自 BAT 和白色脂肪组织 (WAT) 的人类脂肪细胞已经确定了特定的 lncRNA随着BMI和糖尿病的增加而有差异表达和改变。现在， lncRNA-mRNA 调控的计算机测定仍然存在问题（由于缺乏策划资源），并且 对 CMD 及其下游人群的可接触组织（例如血浆）进行大规模验证 缺乏心血管风险。因此，了解 lncRNA 在人类中的作用必须 (1) 与 CMD 相关的人体组织； (2) 识别lncRNA和mRNA表达之间的坐标变化（如 lncRNA调控的可能目标）； (3) 包括lncRNA与CMD表型之间的关联研究 使未来更大规模的 CMD 机制研究成为可能。 在这里，我们假设 lncRNA 在 BAT 与 WAT 中差异表达或与脂肪生成相关 将 (1) 与 CMD 发病机制核心基因的表达相关，以及 (2) 在 CMD 中动态表达 血浆作为心脏代谢扰动的函数，已知会影响 CMD 和心血管疾病（例如， 减肥手术、胰岛素抵抗）。为了解决这个中心假设，我们汇集了我们的初步 人类脂肪组织 RNA-seq 数据具有几个非常独特的资源：(1) 持续的 WAT、BAT 和血浆 从 NIH 临床中心和我们机构的前瞻性资源中收集； (2) NIH 资助的研究 我们对减肥手术前/后的个体进行了非编码 RNA 定量 (U54HL112311)并且有初步数据表明lncRNA随着体重减轻而发生巨大变化； (3) 全人群数据 (n=3100)，包括 CMD、mRNA 测量值和 lncRNA 的可用 RNA 分析。该应用程序基于提供差异化​​候选 lncRNA 的初步数据 以代谢活跃的脂肪表达。它得到了积极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 基因目标。所有数据都将公开并作为共享资源创建。