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: 10338074
• 负责人: JANE E Freedman
• 金额: $ 41.62万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338074
• 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; Persons; 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，糖尿病和参与的脂质和血压失调 - 调查 “心脏代谢疾病”（CMD） - 是心血管疾病的主要因素。尽管长期存在数据 将小型非编码RNA植入CMD，在长的非编码RNA（LNCRNA）方面已知。 动物研究最近提出了LNCRNA在脂质稳态，脂肪生热和 心肌重塑，每种都对CMD至关重要。而动物研究可能会增加对lncrnas的可疑 CMD，在人体组织中的研究必须确定其作用。研究重点是lncRNA表达 人类CMD中心的组织对于了解CMD分子生理的新方面至关重要 及其对心血管健康的下游影响。棕色脂肪组织（蝙蝠），能量中心 支出调节和代谢与人体质量指数（BMI）成反比。初步数据 使用蝙蝠和白色脂肪组织（WAT）的人类脂肪细胞（WAT）从我们的组中确定了特定 随着BMI和糖尿病的增加而表达和改变的LNCRNA。现在， 在计算机确定LNCRNA-MRNA调节中，调节仍然有问题（由于缺乏精选资源），并且 在CMD和下游的人群中，可访问组织（例如等离子体）中的大规模验证 缺乏心血管风险。因此，了解LNCRNA在人类中的作用（1） 在与CMD相关的人体组织中； （2）确定lncRNA和mRNA表达之间的坐标变化（AS lncRNA调控的可能目标）； （3）包括LNCRNA和CMD表型之间的关联研究 为了使CMD中的未来更大的机械研究。 在这里，我们假设LNCRNA在BAT与WAT中的表达不同或与脂肪形成相关 将是（1）与CMD发病机理中心的基因的表达相关，（2）在 血浆是已知会影响CMD和心血管疾病的心脏代谢扰动的函数（例如 减肥手术，胰岛素抵抗）。为了解决这个中心假设，我们将初步汇集在一起 人类脂肪组织RNA-seq数据具有几种非常独特的资源：（1）持续的WAT，BAT和等离子体 来自NIH临床中心和我们机构的潜在资源收集； （2）NIH资助的研究 我们已经进行了非编码RNA定量的肺泡前/肺炎后手术 （U54HL112311），并且具有初步数据，可以在lncrnas中建立巨大的变化，并减轻体重； （3） 人口范围的数据（n = 3100），包括CMD，mRNA测量和LNCRNA的可用RNA 分析。该应用程序基于提供差异化​​的候选LNCRNA的初步数据 在代谢活性脂肪中表达。它是由主动协作和先前收集的样本增强的 从NIH/NHLBI赞助的研究以及创新的生物信息学方法来识别可能的lncRNA 基因靶标。所有数据将公开可用，并作为共享资源创建。