Detection and characterization of cell type-specific extracellular vesicles in obesity-driven hepatocellular carcinoma

肥胖导致的肝细胞癌中细胞类型特异性细胞外囊泡的检测和表征

• 批准号: 9806072
• 负责人: Takahisa Nakamura
• 金额: $ 18.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806072
• 关键词: Affect; Biological Markers; Bone Marrow; Cell Culture Techniques; Cells; Characteristics; Complication; Detection; Development; Devices; Disease; Distant; Environment; Extracellular Space; Fatty acid glycerol esters; Genetic Transcription; Goals; Green Fluorescent Proteins; Hepatocyte; Immune; Immune Cell Activation; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Label; Lead; Lipid Bilayers; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Malignant Neoplasms; Mediating; Methods; Molecular; Monitor; Mus; Nucleic Acids; Obesity; Pathogenesis; Pathogenicity; Pathologic; Population; Prevalence; Primary carcinoma of the liver cells; Production; Proteins; Reproducibility; Risk Factors; Role; Serum; Sphingomyelinase; System; TNF gene; Technology; Time; Tissues; base; cancer cell; cancer risk; cell type; chronic liver inflammation; cytokine; dielectric property; exosome; extracellular vesicles; in vivo; in vivo monitoring; innovation; macrophage; microdevice; microvesicles; monocyte; mouse model; neutrophil; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pandemic disease; protein B; trait; tumor

PROJECT SUMMARY The worldwide prevalence of obesity has reached pandemic proportions. An association between fat accumulation or hepatosteatosis and hepatocellular carcinoma (HCC) development has been long known. Obesity-induced hepatosteatosis, together with its more severe complication nonalcoholic steatohepatitis (NASH), classified as the nonalcoholic fatty liver disease (NAFLD) affects up to 40% of the US population. Based on correlative and bench studies, several mechanisms have been proposed to explain how obesity increase cancer risk. An important finding that accounts for the tumor-promoting effect of obesity is the low- grade, aberrant inflammatory response, which results in the elevated production of cytokines, such as TNF and IL-6. Studies with mouse models demonstrated that obesity-promoted HCC development is dependent on the enhanced production of these inflammatory cytokines. However, critical questions concerning how the aberrant inflammation in obesity is initiated have been yet to be clearly defined. We hypothesize that in obesity, extracellular vesicles (EVs) derived from hepatocytes become pathogenic and drive recipient immune cells, such as neutrophils and monocytes/macrophages, towards abnormal inflammation associated with the development of HCC. To demonstrate this hypothesis, we will establish two novel systems; A) a new mouse line in which specific cell/tissue-derived EVs are selectively labeled with green fluorescent protein (GFP), and B) a simple, yet powerful electrokinetic-based micro-device that can rapidly extract EVs based on their dielectric properties from biofluids with high purity and yield. With these systems, we aim to 1) determine if H-EVs become pathogenic and induce aberrant inflammation leading to HCC, and 2) isolate H-EVs through the novel dielectrophoretic (DEP) technology and assess their pro- inflammatory trait. This study will lead us to demonstrate the pathogenicity of hepatocyte-derived EVs, which potentially provides a novel mechanism for the development of HCC and the EV biomarker for the disease.

项目总结