Role of HCV exosomes in intercellular communication

HCV 外泌体在细胞间通讯中的作用

基本信息

批准号：
10833764
负责人：
Young S. Hahn
金额：
$ 5.77万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2020-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10833764
关键词：
Affect Anti-Inflammatory Agents Antiviral Agents Apoptotic Automobile Driving Binding Biological Markers Bypass CASP3 gene Cell Differentiation process Cells Chronic Chronic Hepatitis C Cirrhosis Clinical Coculture Techniques Data Development Disease Progression Endothelial Cells Equilibrium Fibrosis Frequencies Generations Goals Health Hepatic Hepatic Stellate Cell Hepatitis C Hepatitis C Therapy Hepatitis C virus Hepatocyte Homeostasis Human Immune Immunotherapeutic agent In Vitro Inflammatory Inflammatory Response Life Liver Liver Fibrosis Liver diseases Macrophage Maintenance Mediating Membrane MicroRNAs Molecular Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Persons Plasminogen Inactivators Play Population Pre-Clinical Model Prevention Primary carcinoma of the liver cells Principal Investigator Process Production Profibrotic signal Regulation Reporting Research Risk Role Severities Signal Transduction Signaling Molecule Surface Testing Therapeutic Therapeutic Agents Transforming Growth Factor beta Virus Work chronic liver disease cytokine design end stage liver disease exosome extracellular vesicles humanized mouse immunoregulation in vivo insight intercellular communication liver development liver inflammation monocyte mouse model nanoparticle delivery new therapeutic target novel novel therapeutic intervention peripheral blood prevent programs stellate cell transmission process

项目摘要

Program Director/Principal Investigator (Hahn, Young S.): Project Summary: Chronic HCV infection affects an estimated 3% of the world's population (>180 million people) and is a worldwide health problem causing end-stage liver diseases including hepatocellular carcinoma (HCC). The development of HCV-related HCC occurs by advanced fibrosis or cirrhosis. The clinical outcome of HCV infection and HCC risk depends on a balance between pro- and anti-inflammatory cytokines and the severity of liver inflammation. Our preliminary data show that exosomes released from HCV-infected hepatocytes contain the immunoregulatory molecules such as TGF-β. Importantly, HCV exosmes derived from infected hepatocytes promote intercellular communication with non-parenchymal cells such as Mφ and LSEC. As a result of receiving signaling from HCV exosomes, Mφ and LSEC are differentiated into fibrotic cells, that activate stellate cells and induce the development of liver fibrosis. The overall goal of this project is to define the mechanism by which HCV-derived exosomes from infected hepatocytes drive pro-fibrotic liver microenvironment and explore potential therapeutic agents to prevent liver fibrosis. In Aim 1, we propose to identify key molecular machinery required for the secretion of hepatocyte exosomes after HCV infection in in vitro and in vivo. In Aim 2, we will determine how HCV-derived exosomes induce the activation of fibrotic M2-like Mφ. In Aim 3, we will determine how HCV-derived exosomes induce fibrotic LSEC differentiation and explore a therapeutic strategy for preventing fibrosis. The studies proposed here will break new ground for identifying factors crucial for driving pro-fibrotic liver microenvironment and will help to develop novel therapeutic targets for the prevention of liver fibrosis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

计划主任/首席研究员（Hahn，Young S.）：项目摘要：慢性HCV感染影响了世界人口的3％（> 1.8亿人），并且是一个全球健康问题，导致包括肝细胞癌（HCC）在内的终末期肝病。通过晚期纤维化或肝硬化，与HCV相关的HCC的发展发生。 HCV的临床结果感染和HCC风险取决于促炎和抗炎细胞因子之间的平衡以及肝炎。我们的初步数据表明，由HCV感染的肝细胞释放的外泌体包含免疫调节分子，例如TGF-β。重要的是，源自感染的肝细胞的HCV外观促进与非副作用细胞（如Mφ和LSEC）的细胞间通信。后果从HCV外泌体接收信号，Mφ和LSEC分化为纤维化细胞，激活星状细胞并诱导肝纤维化的发展。该项目的总体目标是通过来自感染的肝细胞的HCV衍生的外泌体驱动促纤维化肝微环境并探索潜在的治疗剂可预防肝纤维化。在AIM 1中，我们建议识别关键分子机械在体外和体内HCV感染后肝细胞外泌体的分泌所必需的。在AIM 2中，我们将确定HCV衍生的外泌体如何诱导纤维化M2样Mφ的激活。在AIM 3中，我们将确定 HCV衍生的外泌体如何诱导纤维化LSEC分化并探索治疗策略防止纤维化。此处提出的研究将破坏确定驾驶至关重要的因素的新基础促纤维性肝微环境，将有助于开发新的治疗靶标，以预防肝脏纤维化。 PHS 398/2590（修订版06/09）页面延续格式页面