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.

项目总结/文摘