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Extracellular Vesiclemediated Regulation of Metabolism

细胞外囊泡介导的代谢调节

基本信息

批准号：
10447851
负责人：
Clair Crewe
金额：
$ 24.9万
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/10447851
关键词：
Adipocytes Adipose tissue Area Biochemical Biological Assay Blood Circulation Cell Communication Cell Culture Techniques Cell model Cell physiology Cells Cessation of life Charge Communication Communications Media Data Endocrine Glands Endothelial Cells Endothelium Event Extracellular Space Fasting Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Glucagon Glycolysis Goals Harvest Health Homeostasis Hormones Hyperplasia Hypoxia Immune Immune response In Vitro Inflammation Intervention Lipids Malignant Neoplasms Measurement Mediating Metabolic Metabolic stress Metabolism MicroRNAs Mitochondria Mitochondrial Proteins Mus Necrosis Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Outcome Pathology Pathway interactions Pharmacology Physiological Physiology Process Production 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 chemical genetics combat exosome extracellular extracellular vesicles glucose metabolism human tissue in vivo insulin secretion intercellular communication macrophage mitochondrial dysfunction mouse model nanosized novel particle prevent 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.

项目总结/文摘