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Exosome platforms for assessment and therapy of chronic liver disease

用于评估和治疗慢性肝病的外泌体平台

基本信息

批准号：
8968550
负责人：
DAVID R BRIGSTOCK
金额：
$ 21.49万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-10 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968550
关键词：
Accounting Adult Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols American Apoptosis Applications Grants Attenuated Binding Biogenesis Biological Biological Markers Biology Blood Blood Circulation Body Fluids Cells Cessation of life Cicatrix Cirrhosis Collection Complex Complex Mixtures Conditioned Culture Media Data Development Diagnosis Diagnostic Disease Distant Economic Burden Ethanol Ethanol dependence Fibrosis Goals Guidelines Harvest Health Health Status Hepatic Stellate Cell Hepatocyte Home environment Homing Image In Vitro Inflammation Integrins Knowledge Lead Ligands Liver Liver Fibrosis Liver diseases Mediating Membrane Messenger RNA Methods MicroRNAs Molecular Molecular Profiling Multivesicular Body Mus Outcome Pathway interactions Patients Population Primary carcinoma of the liver cells Production Proteins Reading Reporting Risk Role Sepsis Serum Severities Site Small Interfering RNA Specimen Stimulus Testing Therapeutic Therapeutic Effect Tissues Treatment Efficacy Urine Vesicle Work alcohol effect base cell type chronic liver disease clay connective tissue growth factor differential expression disease diagnosis extracellular health economics improved in vivo in vivo Model innovation liver biopsy liver injury minimally invasive mortality nanoscale nanosized nanovesicle non-alcoholic novel public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): The broad long-term objective is to improve methods of disease assessment and treatment in the liver. Approximately 5.5 million American adults (i.e., 2-3% of the adult US population) suffer from chronic liver disease. Alcoholic liver disease (ALD) accounts for the largest proportion of chronic liver disease in the West and exacerbates liver injury due to non-alcoholic causes. Alcoholic cirrhosis ranks as the 8th most common cause of mortality in the US and the second leading cause of GI-related deaths. There is an unmet need to improve our arsenal of diagnostic options by using modern molecular approaches to analyze biological specimens that can be collected in a minimally-invasive or non-invasive manner, and a new lead has emerged with the discovery of "exosomes". These are nanovesicles that are secreted by many cell types and which contain a complex mixture of microRNAs, mRNAs and proteins that reflect the transcriptional and/or translational activity of their producer cells. We showed that (i) miRs in circulating exosomes undergo dynamic changes during experimental fibrosis in mice; (ii) expression of fibrosis-related miRs or mRNA in exosomes secreted by hepatic stellate cells (HSC, the principal pro-fibrogenic cell type in the liver) reflects the induction status of fibrogenic pathways within the cells; (iii) expression in HC of molecules regulating exosome biogenesis is ethanol-dependent; (iv) fibrosis-related miRs are exosomally shuttled between HSC and are functional after being taken up by recipient cells; and (v) exosomes from HSC are preferentially taken up by HSC both in vivo and in vitro, highlighting the existence of a novel homing mechanism for HSC-derived exosomes. Thus our overall objective is to establish the role of exosomes in liver disease and their potential role in disease diagnosis or therapy. Our central hypothesis is that exosomes have diagnostic and therapeutic utility in liver disease, including that caused by alcohol. The Aims to test our hypothesis are: Specific Aim 1: Establish ethanol-mediated changes in exosome production and molecular payload. We will determine the effect of ethanol on pathways of exosome biogenesis and secretion in HSC and establish miR signatures in exosomes from the serum of ALD patients Specific Aim 2. Establish mechanisms and therapeutic applications of exosome homing to HSC. We will characterize integrin-mediated interactions between exosomes and HSC and, in an in vivo model of experimental liver fibrosis, establish their role in mediating HSC-specific localization and therapeutic efficacy of exosomes loaded with anti-fibrotic siCTGF. The expected outcome of these exploratory R21 studies will be innovative breakthroughs in the diagnosis and therapy of chronic liver disease by improved understanding and exploitation of exosome function. The rationale underlying the application is that identification of exosomal molecular payloads and intercellular shuttling mechanisms will have direct relevance to disease diagnosis and therapy. The positive impact of these studies is that they will improve the health of millions of people world-wide with ALD and other liver diseases.