Profiling extracellular vesicle cargo in obesity and type 2 diabetes

分析肥胖和 2 型糖尿病中的细胞外囊泡货物

• 批准号: 10234093
• 负责人: Johanna K DiStefano
• 金额: $ 76.3万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10234093
• 关键词: Address; Adipocytes; Adipose tissue; Age; Analysis of Variance; Biological Assay; Body Weight decreased; Body mass index; Cell Communication; Cells; Chronic; Classification; Development; Diabetes Mellitus; Disease remission; Ethnic Origin; Genetic Transcription; Glucose Intolerance; Human; ITGAM gene; Individual; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knowledge; Lead; Link; Lipids; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Metabolic; MicroRNAs; Mining; Modeling; Molecular; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obese Mice; Obesity; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Plasma; Play; Proteins; Proteomics; Publishing; RNA; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Sample Size; Sampling; Sampling Studies; Shotguns; Source; Thinness; Tissue Sample; Tissues; Transcript; Validation; Vesicle; Visceral; Work; adipokines; bariatric surgery; cell type; cellular targeting; cohort; diabetic; drug development; experience; extracellular vesicles; fatty acid-binding proteins; glucose metabolism; glucose tolerance; glycemic control; improved; macrophage; member; morphogens; new therapeutic target; obese patients; obese person; protein expression; restoration; sex

PROJECT SUMMARY/ABSTRACT Obesity diabetes adipose spectrum Emerging is linked with heightened risk of insulin resistance and type 2 (T2D) Obesity is also associated attributed primarily to visceral tissue (VAT), which increases T2D risk; however, the precise molecular mechanisms underlying the inflammatory and metabolic mediators of dysglycemia in obesity remain poorly studies support a role for extracellular vesicles (EVs) in both T2D and obesity. metabolic abnormalities, including . with chronic low-grade inflammation, of understood. EVs are a heterogeneous class of membrane vesicles that participate in cell-cell communication through exchange of proteins, lipids, and nucleic acids. Circulating and adipocyte-derived EVs have been shown to increase in obesity, decrease following weight reduction, and correlate with restoration of glycemic control in T2D patients following bariatric surgery. Adipose-derived EVs may also mediate T2D pathogenesis. We hypothesize that protein and RNA cargo of circulating EVs contribute to metabolic derangements in obesity, and correspondingly, to improvements in glucose metabolism associated with bariatric surgery. To address this hypothesis, we propose a strategy to identify EV-derived protein and RNA profiles associated with obesity- related T2D. In Aim 1, we will derived transcripts assess protein and RNA (lncRNA, miRNA, and mRNA) content in plasma- EVs obtained from T2D (N=60) and normoglycemic (N=60) individuals with obesity. Proteins and showing T2D-associated patterns will be analyzed in an independent study sample (N=120). Completion of this aim will result in the identification and validation of protein and RNA profiles associated with T2D in extreme obesity. In Aim 2, we propose to determine whether T2D-associated protein and RNA signatures emanate from VAT by evaluating cargo (protein and RNA) isolated from immuno-selected fractions of EVs and from EVs obtained from VAT-conditioned media. Determining involved we will establish whether T2D-associated signatures are lost in patients who experience T2D remission following bariatric surgery, but retained in those who remain diabetic, even in the presence of significant weight loss. In specific, we will measure T2D-associated protein and RNA profiles identified and validated in Aim 1 in individuals who whether VAT is the in the pathogenesis of T2D will provide a cellular target for further studies. In Aim 3, source of EVs experience T2D remission and those who remain diabetic. Completion of this understanding The combination of plasma and VAT samples from bariatric surgery patients and state-of-the-art molecular characterization provides a unique opportunity to identify those patients likely to receive the greatest benefit from bariatric surgery, improve our understanding of T2D pathogenesis, and perhaps lead to the development of drugs that mimic effects of surgery. of the mechanisms underlying T2D remission following aim is expected to enhance our bariatric surgery.

项目总结/摘要 肥胖 糖尿病 脂肪 频谱 新兴 与胰岛素抵抗和2型糖尿病的风险增加有关 (T2D)肥胖也与主要归因于内脏 组织（VAT），这会增加T2D风险;然而， 肥胖症中代谢障碍的炎症和代谢介质仍然很差， 研究支持细胞外囊泡（EV）在T2D和肥胖症中的作用。 代谢 异常， 包括 .慢性低度炎症， 的理解。 电动汽车是一个 细胞膜囊泡是一类异质的膜囊泡，通过交换 蛋白质、脂质和核酸。循环和脂肪细胞来源的EV已被证明增加， 肥胖，体重减轻后降低，并与T2D患者的血糖控制恢复相关 在减肥手术后。脂肪来源的EV也可能介导T2D发病机制。我们假设 循环EV的蛋白质和RNA货物有助于肥胖症的代谢紊乱， 相应地，与减肥手术相关的葡萄糖代谢的改善。为了解决这个 假设，我们提出了一种策略，以确定EV衍生的蛋白质和RNA谱与肥胖相关- T2D相关在目标1中，我们 衍生 成绩单 评估血浆中的蛋白质和RNA（lncRNA、miRNA和mRNA）含量- EV从T2 D（N = 60）和血糖正常（N = 60）肥胖个体中获得。蛋白质和 显示T2D相关模式，将在独立研究样本中进行分析（N = 120）。 这一目标的完成将导致鉴定和验证与以下相关的蛋白质和RNA谱： T2D在极度肥胖中的作用在目的2中，我们提出确定T2D相关蛋白和RNA是否 通过评估从免疫选择级分分离的货物（蛋白质和RNA），从VAT产生特征 的EV和来自从VAT条件培养基获得的EV。确定 我们将建立 在肥胖治疗后出现T2D缓解的患者中，T2D相关特征是否丢失 手术，但保留在那些谁仍然是糖尿病，即使在存在显着的体重减轻。具体来说， 我们将测量目标1中鉴定和验证的T2D相关蛋白和RNA谱， 增值税是否是 在T2D发病机制中的作用将为进一步研究提供细胞靶点。在目标3中， 源 的 EVs 2型糖尿病患者和那些仍然患有糖尿病的人。完成本 理解的结合 来自减肥手术患者的血浆和VAT样本以及最先进的分子表征 提供了一个独特的机会，以确定那些可能从减肥中获得最大益处的患者 手术，提高我们对T2D发病机制的理解，并可能导致药物的开发， 模仿手术效果 的 的 机制 底层 T2d 缓解 以下 我们的目标是提高我们的 减肥手术