Extracellular Vesiclemediated Regulation of Metabolism

细胞外囊泡介导的代谢调节

基本信息

批准号：
10666550
负责人：
Clair Crewe
金额：
$ 23.49万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666550
关键词：
Adipocytes Adipose tissue Area Beta Cell Biochemical Biological Assay Cell Communication Cell Culture Techniques Cell model Cell physiology Cell secretion Cells Cessation of life Charge Chemicals Circulation Communication Communications Media Data Endocrine Glands Endothelial Cells Endothelium Event Fasting Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Genetic Glucagon Goals Harvest Health Homeostasis Hormones Hyperplasia Hypoxia Immune Immune response In Vitro Inflammation Intervention Lipids Macrophage Malignant Neoplasms Measurement Mediating Metabolic Metabolic stress Metabolism MicroRNAs Mitochondria Mus Necrosis Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutrient availability Obesity Organ Outcome Pathology Pathway interactions Physiological Physiology Process Production Proliferating Proteins Public Health Publishing Regulation Repression Research Role Serum Signal Pathway Signal Transduction Signaling Protein Specialist Stress TNF gene Techniques Testing Tissue Expansion Tissues Training Vascular Endothelial Growth Factors Vesicle Work angiogenesis cell type combat exosome extracellular extracellular vesicles glucose metabolism human tissue immunoregulation in vivo insulin secretion intercellular communication mitochondrial dysfunction mouse model nanosized novel particle pharmacologic prevent programs skills stressor trafficking tumor microenvironment vesicular release

项目摘要

Project Summary/Abstract Adipose tissue dysfunction is at the forefront of metabolic disturbances in obesity and type II diabetes, making it a promising target for pharmacological intervention. This active, energy-sensing, endocrine organ secretes number of factors that have profound effects on systemic metabolism, in addition to its role in sequestering potentially toxic lipids species. Proper function of adipose tissue is maintained by cross-talk between resident tissue cells including adipocytes, endothelial cells, immune cells and fibroblasts, a process that is disrupted in the obese condition. The efficiency at which the adipose tissue responds to nutrient stresses can mean the difference between sustained whole-body metabolic homeostasis or pathology. My recently published work describes the finding that cells in adipose tissue exchange extracellular vesicles (EV) that are rich in signaling proteins, lipids, and, potentially miRNAs. These transfer events are dominated by an endothelial-to- adipocyte axis; however, adipocytes also secrete EVs that are taken up but other cells in the tissue such as macrophages or mural cells. Furthermore, we found that under the energetic stress of fasting, endothelial cell EV secretion is enhanced and targeted to adipocytes. This work has opened up vast potential for the discovery of novel signaling pathways between these cells that may provide an understanding of what pathways support healthy vs maladaptive adipose tissue remodeling under the nutrient stress of obesity or fasting. Preliminary data suggests that endothelial cell EVs support adipocyte ATP production during mitochondrial energetic stress by increasing adipocyte glycolytic reserve. Furthermore, adipocyte EV production is enhanced in the context of mitochondrial dysfunction, which we predict will regulate systemic metabolism. Thus, I hypothesize that under energetic stress, adipose tissue endothelial cells and adipocytes work synergistically through EV production to modulate whole body metabolism. The first Aim will test the hypothesis that endothelial cell EVs reprogram adipocyte metabolism to promote efficient adaptation of the adipocyte to metabolic stress. Aim 2 will evaluate the concept that energetic stress stimulates adipocytes to secrete EVs that alter systemic metabolism. The general approach will take advantage of both in vitro cell culture techniques as well as recently generated mouse models of cell-specific mitochondrial dysfunction or cell-specific suppression of EV production. This proposal will give me the opportunity to be trained in metabolic tracing techniques, mouse physiology, and human tissue acquisition by highly skilled specialists in the Scherer lab and throughout UT Southwestern. Successful completion of these aims has the potential to open a new area of research to decipher EV-mediated signaling pathways in metabolic regulation.

项目概要/摘要脂肪组织功能障碍是肥胖和 II 型糖尿病代谢紊乱的首要原因，使其成为药物干预的有希望的目标。这种活跃的、能量感应的内分泌器官分泌多种对全身代谢有深远影响的因子，除了在隔离潜在有毒的脂质物质。脂肪组织的正常功能是通过串扰维持的驻留组织细胞（包括脂肪细胞、内皮细胞、免疫细胞和成纤维细胞）之间的相互作用，这一过程在肥胖情况下被破坏。脂肪组织对营养应激的反应效率可以是指持续的全身代谢稳态或病理学之间的差异。我最近发表的这项工作描述了脂肪组织中的细胞交换富含细胞外囊泡（EV）的发现信号蛋白、脂质和潜在的 miRNA。这些转移事件由内皮细胞主导脂肪细胞轴；然而，脂肪细胞也会分泌 EV，但组织中的其他细胞（例如巨噬细胞或壁细胞。此外，我们发现在禁食的能量压力下，内皮细胞 EV 分泌增强并靶向脂肪细胞。这项工作开启了巨大的潜力这些细胞之间新的信号传导途径的发现可能有助于了解什么在肥胖营养压力下支持健康脂肪组织重塑与适应不良脂肪组织重塑的途径或禁食。初步数据表明，内皮细胞 EV 支持脂肪细胞 ATP 的产生通过增加脂肪细胞糖酵解储备来缓解线粒体能量应激。此外，脂肪细胞 EV 的产生在线粒体功能障碍的情况下会增强，我们预测这将调节全身代谢。因此，我假设在能量压力下，脂肪组织内皮细胞和脂肪细胞发挥作用通过 EV 生产协同调节全身新陈代谢。第一个目标将测试假设内皮细胞 EV 重新编程脂肪细胞代谢以促进脂肪细胞的有效适应脂肪细胞对代谢应激的影响。目标 2 将评估能量压力刺激脂肪细胞的概念分泌改变全身代谢的 EV。一般方法将利用体外细胞培养技术以及最近生成的细胞特异性线粒体功能障碍或细胞特异性的小鼠模型抑制电动汽车生产。该提案将使我有机会接受代谢追踪培训 Scherer 实验室的高技能专家负责技术、小鼠生理学和人体组织采集整个德克萨斯大学西南分校。成功完成这些目标有可能开辟一个新领域研究破译 EV 介导的代谢调节信号通路。