Determining the function of IRF5 tumor suppressor in HCV pathogenesis

确定 IRF5 抑癌基因在 HCV 发病机制中的功能

基本信息

批准号：
9147052
负责人：
Betsy J Barnes
金额：
$ 21.99万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2015-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9147052
关键词：
Address Apoptosis Apoptotic Blood-Borne Pathogens Cells Cessation of life Chronic Chronic Hepatitis C Cirrhosis Complex DNA Damage Data Development Diagnosis Down-Regulation Drug resistance Exhibits Family Fibrosis Foundations Genes Health Services Accessibility Hepatitis C Hepatitis C virus Hepatocyte Human Immunofluorescence Immunologic Individual Infection Interferon Suppression Interferons Link Literature Liver Liver diseases Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Molecular Target Oncogenes Oncogenic Oncogenic Viruses Pathogenesis Patient Noncompliance Play Primary carcinoma of the liver cells Proteins Public Health Regimen Regulation Relative (related person)Replicon Reporting Risk Factors Role Signal Pathway Signal Transduction Specimen Staging Staining method Stains Survival Rate Testing Tissue Microarray Translations Tumor Suppressor Proteins Vaccines Variant Viral Viral Proteins Virus Virus Replication abstracting anti-hepatitis C base cancer type cell growth chemokine chronic liver disease clinically relevant clinically significant combat cost cytokine fascinate gene repression global health hepatoma cell human tissue migration new therapeutic target novel pathogen patient population prophylactic public health relevance success transcription factor tumor tumorigenesis virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Abstract Infection with Hepatitis C virus (HCV), an important human blood-borne pathogen, is the most significant risk factor for the development of hepatocellular carcinoma (HCC), a major liver malignancy and cancer type worldwide. Eighty-five percent of HCV infections become chronic with sequelae including fibrosis, cirrhosis and eventually HCC, a highly malignant tumor with current average survival rates of less than 1 year following diagnosis. Currently, there are no prophylactic vaccines against HCV, and although anti-HCV therapies have advanced within the last two years, treatment success has been limited due to relative efficacy of different regimens in different patient populations, adverse drg effects resulting in patient non-adherence, rapid emergence of drug-resistant variants, access to care and cost of therapy. With an estimated 200 million chronically infected individuals world-wide and a reported 350,000 deaths annually, hepatitis C has emerged as a serious global health burden. Therefore, a better understanding of the pathophysiological mechanisms modulating HCV pathogenesis are sorely warranted to address this global crisis and identify new molecular targets. In this application, we will address the role of interferon regulatory facto 5 (IRF5) in HCV pathogenesis mechanisms. IRF5 belongs to the interferon regulatory factor (IRF) family of transcription factors that play critical roles in virus-, IFN- and DNA damage-induced signaling pathways. Recently, new facets of IRF5 in regulating cell growth, apoptosis and tumor suppressor function have emerged. Importantly, IRF5 has now been implicated in several human cancers. Surprisingly, its role in HCV pathogenesis has not been explored to-date. Although IRF5 is normally expressed in hepatocytes, we have discovered that IRF5 expression is dramatically down-regulated in HCV replicon bearing hepatoma cells and further IRF5 over-expression suppresses HCV translation and replication. Importantly, we provide critical evidence that IRF5 suppresses the activity of the oncogene autotaxin (ATX), previously reported as a contributing factor in HCV-associated oncogenesis. This suggests that IRF5 may serve as a negative restriction factor in HCV pathogenesis. These compelling evidences argue in favor of a tumor-suppressive role for IRF5 in HCV replication and pathogenesis. The proposed studies will delineate the molecular mechanisms of IRF5 regulation during HCV infection and address the functional implications of its modulation and signaling in HCV pathogenesis. Findings from these studies will identify new molecular targets to combat chronic HCV infection.

描述（由适用提供）：丙型肝炎病毒（HCV）的抽象感染是一种重要的人类血液传播病原体，是全球肝细胞癌（HCC）发展的最重要的危险因素，这是全球主要的肝脏恶性肿瘤和癌症类型。 HCV感染的百分之八十五持续了后遗症，包括纤维化，肝硬化和最终HCC，这是一种高度恶性肿瘤，当前平均存活率在诊断后少于1年。目前，尚无针对HCV的预防性疫苗，尽管抗HCV疗法在过去两年内已进展，但由于不同患者种群中不同治疗疗法的相对有效性，治疗成功受到限制，导致患者不粘附，导致药物耐药性变体的快速出现，可以接受护理和治疗成本。据估计，全球范围内有2亿长期感染的人，每年有350,000人死亡，乙型肝炎已成为严重的全球健康伯恩。因此，对调节HCV发病机理的病理生理机制的更好理解是有必要解决这一全球危机并确定新分子靶标的的。在此应用中，我们将解决干扰素调节性事实5（IRF5）在HCV发病机理中的作用。 IRF5属于在病毒，IFN和DNA损伤诱导的信号通路中起关键作用的转录因子的干扰素调节因子（IRF）家族。最近，IRF5在调节细胞生长，凋亡和肿瘤抑制功能方面的新方面已经出现。重要的是，IRF5现已在几种人类癌症中实施。令人惊讶的是，其在HCV发病机理中的作用尚未探讨及时。尽管IRF5通常在肝细胞中表达，但我们发现IRF5表达在HCV复制肝癌细胞中被显着下调，而进一步的IRF5过表达抑制了HCV的翻译和复制。重要的是，我们提供的关键证据表明，IRF5抑制了癌基因自身Xt蛋白（ATX）的活性，此前据报道是HCV相关肿瘤发生的促成因素。这表明IRF5可能是HCV发病机理中的负限制因子。这些引人注目的证据表明，IRF5在HCV复制和发病机理中具有肿瘤抑制作用。拟议的研究将描述HCV感染过程中IRF5调控的分子机制，并解决其调节和信号传导在HCV发病机理中的功能意义。这些研究的发现将确定新的分子靶标，以打击慢性HCV感染。