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: 10684629
• 负责人: Johanna K DiStefano
• 金额: $ 75.34万
• 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/10684629
• 关键词: Address; Adipocytes; Adipose tissue; Age; Analysis of Variance; Biological Assay; Body Weight decreased; Body mass index; Cell Communication; Cells; Chronic; Classification; Conditioned Culture Media; Development; Diabetes Mellitus; Disease remission; Ethnic Origin; Genes; Genetic Transcription; Glucose Intolerance; Human; ITGAM gene; Individual; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knowledge; Lead; Link; Lipids; Macrophage; Mass Spectrum Analysis; Measures; Mediating; Mediator; Membrane; Messenger RNA; Metabolic; MicroRNAs; Mining; Modeling; Molecular; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obese Mice; Obesity; Ontology; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Plasma; Play; Proteins; Proteomics; Publishing; Quantitative Reverse Transcriptase PCR; RNA; Risk; Risk Factors; Role; Sample Size; Sampling; Sampling Studies; Shotguns; Source; Thinness; Tissue Sample; Tissues; Transcript; Validation; Vesicle; Visceral; Work; adipokines; bariatric surgery; candidate validation; cell type; cellular targeting; cohort; diabetic; drug development; experience; extracellular vesicles; fatty acid-binding proteins; glucose metabolism; glucose tolerance; glycemic control; improved; lonely individuals; member; morphogens; new therapeutic target; obese patients; obese person; protein expression; restoration; sex; verification and validation

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.

项目摘要/摘要 肥胖 糖尿病 脂肪 光谱 新兴 与胰岛素抵抗和类型2的风险增加有关 （T2D）肥胖也主要归因于内脏 组织（增值税），增加T2D风险；但是，依据的精确分子机制 肥胖症中血糖症的炎症和代谢介质仍然很差 研究支持T2D和肥胖症中细胞外囊泡（EV）的作用。 代谢 异常， 包括 。慢性低度炎症， 理解。 电动汽车是一个 通过交换来参与细胞细胞通信的异质类膜囊泡 蛋白质，脂质和核酸。循环和脂肪细胞衍生的电动汽车已显示出增加 肥胖，减轻体重后减少，与T2D患者的血糖控制的恢复相关 减肥手术后。脂肪来源的电动汽车也可能介导T2D发病机理。我们假设这一点 循环电动汽车的蛋白质和RNA货物有助于肥胖的代谢危险，并且 相应地，改善与减肥手术相关的葡萄糖代谢。解决这个问题 假设，我们提出了一种策略，以鉴定与肥胖相关的EV衍生蛋白和RNA谱。 相关T2D。在AIM 1中，我们将 衍生的 成绩单 评估血浆中蛋白质和RNA（lncRNA，miRNA和mRNA）含量 从T2D（n = 60）和肥胖症患者的正常血糖（n = 60）获得的电动汽车。蛋白质和 显示与T2D相关的模式将在独立的研究样本中进行分析（n = 120）。 完成此目标的完成将导致对与蛋白质和RNA曲线相关的识别和验证 T2D极端肥胖。在AIM 2中，我们建议确定与T2D相关蛋白和RNA是否 通过评估从免疫选择的部分分离出的货物（蛋白质和RNA），从增值税中发出的特征 电动汽车和从增值税调节媒体获得的电动汽车的摄入量。确定 参与我们将建立 在减肥后经历T2D缓解的患者中，与T2D相关的签名是否丢失 手术，但仍保留在糖尿病患者中，即使在大量体重减轻的情况下也是如此。具体而言 我们将测量与T2D相关的蛋白质和RNA曲线，在AIM 1中识别和验证的个人 增值税是否是 在T2D的发病机理中，将为进一步研究提供一个细胞靶标。在AIM 3中， 来源 的 电动汽车 体验T2D缓解和那些保持糖尿病的人。完成此操作 了解结合 减肥手术患者的血浆和增值税样品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中获得最大收益的患者 手术，提高我们对T2D发病机理的理解，也许会导致药物的发展 模仿手术的作用。 的 这 机制 潜在的 T2D 缓解 下列的 目标有望增强我们的 减肥手术。

项目成果

COVID-19 patients with obesity at risk for worse outcomes despite younger age and fewer inflammatory derangements.

• DOI: 10.1016/j.soard.2021.06.006
• 发表时间: 2021-10
• 期刊: Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery
• 作者: Le Guen CL;King NA;Zhao H;Renza-Stingone EP;Gerhard GS;Soans RS
• 通讯作者: Soans RS