Mechanisms of T cell dysfunction in Hepatitis C virus persistence

丙型肝炎病毒持续存在中 T 细胞功能障碍的机制

基本信息

批准号：
7317904
负责人：
HENRY Thomas RADZIEWICZ
金额：
$ 12.83万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7317904
关键词：
5-(6)-carboxyfluorescein diacetate succinimidyl ester Accounting Activities of Daily Living Acute Hepatitis C Adverse effects Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Response Apoptosis Attenuated Award B-Lymphocytes Binding Biological Assay Blocking Antibodies CD28 gene CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cells Cellular Immunity Chimeric Proteins Chronic Chronic Hepatitis Cirrhosis Class Commit Communicable Diseases Communication Cultured Cells Data Dendritic Cells Development Differentiation Antigens Disease Progression Down-Regulation Environment Evaluation Extracellular Domain Failure Family Fibrosis Frequencies Functional disorder Funding Genome Genotype Goals HIV HIV Infections HLA-A2 Antigen HLA-DR Antigens Hepatitis C Hepatitis C virus Hepatocyte Human IL7R gene Immune Immune response Immunohistochemistry Immunology In Vitro Individual Infection Inflammatory Interferons Ligands Link Liver Liver Function Tests Liver diseases Lung Lymphocytic choriomeningitis virus Measures Mediating Medicine Modeling Monoclonal Antibody HuM291 Muromonab-CD3 Mus Mutation Pathogenesis Pathway interactions Patients Persons Phenotype Play Polymerase Chain Reaction Predisposition Primary carcinoma of the liver cells Production Protein Overexpression Psoriasis vulgaris Regulation Research Rheumatoid Arthritis Ribavirin Role SELL gene Scientist Score Serum Signal Transduction Signaling Molecule Site Spleen Staining method Stains System T-Cell Activation T-Cell Receptor T-Lymphocyte Tendon Transfer Testing Time Tissues United States Universities Vaccine Research Viral Viral Load result Viral Proteins Viral hepatitis Viremia Virus Virus Diseases Work annexin A5 antiretroviral therapy base career cytokine enzyme linked immunospot assay exhaust exhaustion functional restoration hepatoma cell improved improved functioning intrahepatic liver biopsy liver function liver infection liver transplantation medical specialties member monocyte mouse model peripheral blood programs receptor response virus core

项目摘要

DESCRIPTION (provided by applicant): Henry Radziewicz is a highly motivated scientist at Emory University with a specialty in Infectious Diseases Medicine, whose overall goal is to develop an independent scientific career with a research program focused on understanding the pathogenesis of chronic viral infections such as hepatitis C virus (HCV). Why does the adaptive immune response to HCV fail in the majority of infected persons? His immediate goal is to receive funding through a research career award (K08) that will enable sufficient protected time for didactics and research to enable this development. His long-term goal is to discover and test better treatments of chronic viral illness with the improved understanding of their pathogenesis. HCV infects 150-200 million persons and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has become the major cause of liver transplantation in the United States. Current therapies for HCV are very difficulty to tolerate due to disabling side-effects, require prolonged treatment, and are only successful in approximately half of treated patients for the major genotype in the US. Better therapies are needed. Recently, several new members of the B7/CD28 family of co-inhibitory molecules have been discovered, and may play important roles in modulating the immune responses to chronic viral infections. One pair of molecules, PD-1 and its ligand PD-L1 has demonstrated a critical role in the immune response to chronic murine LCMV infection. Blockade of PD-1/PD-L1 enhanced the response of exhausted T cells in this model, and treated mice were able to clear infection from serum, liver, and lung. We hypothesize that an inability to clear HCV viremia in the majority of infected patients is due to overexpression of the PD-1/PD-L1 co-inhibitory system. In conjunction with a research career award, Henry would like to evaluate this system in humans with chronic HCV, and to test if inhibiting this system improves the function of HCV specific CD8+ T cells. Guided by top scientists, Arash Grakoui and Rafi Ahmed, Henry's proposed 4-year program will include one year of didactics in basic immunology and signal transduction, followed by three lab-based, research concentrated years. Emory University is committed to help Henry reach his goal of becoming a top scientist, and the environment at Emory and the Vaccine Research Center is a wonderful environment for a young scientist to flourish.

描述（由申请人提供）：亨利·拉德齐维奇（Henry Radziewicz）是埃默里大学（Emory University）的一位高度积极进取的科学家，具有传染病医学专业，其总体目标是通过一项研究计划发展独立的科学生涯，旨在理解诸如肝炎病毒（HCV）等慢性病毒感染的发病机理。为什么大多数受感染者的适应性免疫反应失败？他的近期目标是通过研究职业奖（K08）获得资金，该奖项将为教学和研究提供足够的保护时间，以实现这一发展。他的长期目标是通过对其发病机理的了解，发现和测试更好地治疗慢性病毒疾病。 HCV感染了150-200万人，并引起慢性肝炎，肝硬化和肝细胞癌。它已成为美国肝移植的主要原因。当前的HCV疗法由于致残的副作用，需要延长治疗而难以忍受，并且仅在大约一半的接受治疗的患者中成功地用于美国主要基因型。需要更好的疗法。最近，已经发现了B7/CD28家族的几个新成员，并可能在调节对慢性病毒感染的免疫反应中起重要作用。一对分子PD-1及其配体PD-L1在对慢性鼠LCMV感染的免疫反应中表现出至关重要的作用。 PD-1/PD-L1的阻断增强了该模型中耗尽的T细胞的反应，并且处理的小鼠能够清除血清，肝脏和肺部的感染。我们假设无法在大多数感染患者中清除HCV病毒血症，这是由于PD-1/PD-L1共抑制系统的过表达。与研究职业奖一起，亨利想评估患有慢性HCV的人类的该系统，并测试抑制该系统是否改善了HCV特定的CD8+ T细胞的功能。亨利（Henry）提议的4年计划将在顶级科学家Arash Grakoui和Rafi Ahmed的指导下，包括一年的基本免疫学和信号转导研究，然后是三个基于实验室的研究集中年份。埃默里大学（Emory University）致力于帮助亨利（Henry）达到成为顶级科学家的目标，而埃默里（Emory）和疫苗研究中心的环境是年轻科学家蓬勃发展的绝佳环境。