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