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: 10018896
• 负责人: Johanna K DiStefano
• 金额: $ 72.24万
• 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/10018896
• 关键词: Address; Adipocytes; Adipose tissue; Age; Analysis of Variance; Biological Assay; Body Weight decreased; 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; new therapeutic target; 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.

项目概要/摘要 肥胖 糖尿病 脂肪 光谱 新兴 与胰岛素抵抗和 2 型胰岛素抵抗风险增加有关 (T2D) 肥胖也主要归因于内脏 组织（增值税），这会增加 T2D 风险；然而，其背后的精确分子机制 肥胖者血糖异常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。 新陈代谢的 异常， 包括 。患有慢性低度炎症， 的理解。 电动汽车是 通过交换参与细胞间通讯的异质类膜囊泡 蛋白质、脂质和核酸。循环和脂肪细胞衍生的 EV 已被证明会增加 肥胖、体重减轻后减少以及与 T2D 患者血糖控制恢复相关 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 货物会导致肥胖的代谢紊乱，以及 相应地，与减肥手术相关的葡萄糖代谢的改善。为了解决这个问题 假设，我们提出了一种策略来识别与肥胖相关的 EV 衍生蛋白和 RNA 谱 - 相关 T2D。在目标 1 中，我们将 衍生的 成绩单 评估血浆中的蛋白质和 RNA（lncRNA、miRNA 和 mRNA）含量 从 T2D (N=60) 和血糖正常 (N=60) 肥胖个体获得的 EV。蛋白质和 显示 T2D 相关模式将在独立研究样本 (N=120) 中进行分析。 完成这一目标将导致与相关的蛋白质和 RNA 图谱的鉴定和验证 极度肥胖的 T2D。在目标 2 中，我们建议确定 T2D 相关蛋白和 RNA 是否 通过评估从免疫选择组分中分离出的货物（蛋白质和 RNA），从 VAT 中产生特征 的电动汽车和从增值税条件媒体获得的电动汽车。确定 我们将参与其中 减肥后 T2D 缓解的患者中 T2D 相关特征是否会丢失 手术，但保留在那些仍然患有糖尿病的人身上，即使体重明显减轻。具体来说， 我们将测量目标 1 中确定和验证的 T2D 相关蛋白和 RNA 谱： 是否增值税 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， 来源 的 电动汽车 经历 T2D 缓解的人和仍然患有糖尿病的人。完成此 理解 的组合 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来识别那些可能从减肥治疗中获得最大益处的患者 手术，提高我们对 T2D 发病机制的了解，并可能导致药物的开发 模拟手术的效果。 的 这 机制 潜在的 T2D 缓解 下列的 预计目标是增强我们的 减肥手术。