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Hepatocyte-derived extracellular vesicles in alcoholic liver disease

酒精性肝病中肝细胞源性细胞外囊泡

基本信息

批准号：
10205947
负责人：
Ariel Feldstein
金额：
$ 58.04万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10205947
关键词：
Address Alcoholic Fatty Liver Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic steatohepatitis Animal Model Bar Codes Biological Markers Biology Blood Blood Circulation Cell Communication Cells Cellular biology Chronic Country DNA analysis DNA biosynthesis Data Deoxyribonucleotides Development Diagnosis Disease Disease Progression Effector Cell Encapsulated Enzymes Fatty Liver Fibrosis Generations Genes Hepatic Hepatic Stellate Cell Hepatocyte Human Infiltration Inflammasome Inflammation Inflammatory Interleukin-17 Investigation Lipids Liquid substance Liver Liver Fibrosis Macrophage Activation Mediating Messenger RNA MicroRNAs Mitochondrial DNA Modeling Molecular Morbidity - disease rate Mus Organelles Oxides Pathologic Pathology Pathway Analysis Pathway interactions Patients Pattern Penetration Phenotype Plasma Ploidies Process Proteins RNA Role Severity of illness Signal Pathway Signal Transduction Small Interfering RNA Staging Sterility Stress Surface Tail Testing Therapeutic Toll-like receptors Translations United States Untranslated RNA Veins base chronic alcohol ingestion chronic liver disease design efficacious treatment exosome extracellular extracellular vesicles in vitro Assay in vivo liver biopsy macrophage mortality mouse model nonalcoholic steatohepatitis noninvasive diagnosis novel prevent response therapeutic RNA transcriptome sequencing transcriptomics vesicular release

项目摘要

Alcoholic liver disease (ALD) continues to be a devastating disease in the United States and many other countries with the global mortality estimated to exceed 0.7 million per year. Chronic ethanol consumption results in lipid accumulation in hepatocytes and their organelle stress leading to inflammation and fibrosis in the progression of ALD. The crosstalk between hepatocytes and non- parenchymal cells - including hepatic macrophages (HMs) and hepatic stellate cells (HSCs) - is crucial to this process. However, the molecular mechanisms and signaling pathways involved in the crosstalk between lipid overloaded hepatocytes and non-parenchymal cells, remain incompletely understood. In particular, the mechanisms by which this crosstalk facilitates or regulates a transition from chronic asymptomatic alcoholic steatohepatitis (ASH) to fatal alcoholic hepatitis (AH) is a central issue for designing efficacious novel treatments for this devastating disease. While focused on the investigation of cell-to-cell communication we recently revealed that damaged hepatocytes release extracellular vesicles (EVs) and these EVs circulate in the blood in mouse models of ALD. EVs are efficiently internalized into target cells and transfer their cargo including miRNAs. The later is a key mechanism by which encapsulated miRNAs in EVs (EV-miRNAs) serve as “functional extracellular RNAs” to regulate protein translation in target cells. EVs also contain sterile danger signal known as damage-associated molecular patterns (DAMPs). We found that EVs derived from hepatocytes from AH mice are enriched in mitochondrial DNA (mtDNA) that contribute to activation of an inflammatory process. Further, our pathway analysis of RNA-seq data comparing AH vs. preceding chronic (c)ASH mouse livers, identifies EV as one of the most significantly upregulated pathways. Based on these results, we propose the central hypothesis that EVs with a quantitatively and qualitatively distinct cargo are released from damaged hepatocytes in AH vs. preceding cASH to induce unique cellular crosstalk in the genesis of the AH pathologic phenotype. We also hypothesize that plasma EV analysis serves as a liquid liver biopsy providing a barcode for diagnosis and staging of ALD severity. To investigate these hypotheses our proposal has the following SPECIFIC AIMS. 1) Determine the role of EVs and their cargo derived from hepatocytes as barcodes for a transition from asymptomatic cASH to AH in murine models and human ALD. 2) Dissect the mechanisms involved in EV-mediated cell-to-cell communication in the cASH to AH transition. To address these central issues, we have put together a MPI investigative team with expertise in EV biology, ALD pathology, development of unique animal models, human ALD, and RNA therapeutics.

酒精性肝病（ALD）在美国和许多国家仍然是一种毁灭性的疾病