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

• 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
• 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

 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（由申请人提供）：摘要丙型肝炎病毒（HCV）是一种重要的人类血源性病原体，感染是肝细胞癌（HCC）发展的最重要的危险因素，肝细胞癌是世界范围内主要的肝脏恶性肿瘤和癌症类型。 85% 的 HCV 感染会转为慢性，并伴有后遗症，包括纤维化、肝硬化，最终发展为 HCC，这是一种高度恶性肿瘤，目前诊断后的平均存活率不到 1 年。目前，还没有针对 HCV 的预防性疫苗，尽管抗 HCV 疗法在过去两年内取得了进展，但由于不同治疗方案在不同患者群体中的相对疗效、不良药物效应导致患者不依从、耐药变异迅速出现、获得护理和治疗成本等原因，治疗成功率有限。据估计，全世界有 2 亿慢性感染者，每年有 35 万人死亡，丙型肝炎已成为严重的全球健康负担。因此，迫切需要更好地了解调节 HCV 发病机制的病理生理机制，以应对这一全球危机并确定新的分子靶点。在此应用中，我们将探讨干扰素调节因子 5 (IRF5) 在 HCV 发病机制中的作用。 IRF5 属于转录因子干扰素调节因子 (IRF) 家族，在病毒、IFN 和 DNA 损伤诱导的信号通路中发挥关键作用。最近，IRF5 在调节细胞生长、细胞凋亡和肿瘤抑制功能方面的新方面已经出现。重要的是，IRF5 现在已与多种人类癌症有关。令人惊讶的是，迄今为止尚未探讨其在 HCV 发病机制中的作用。尽管IRF5通常在肝细胞中表达，但我们发现IRF5表达在携带HCV复制子的肝癌细胞中显着下调，并且IRF5进一步过度表达抑制HCV翻译和复制。重要的是，我们提供了关键证据，证明 IRF5 抑制癌基因自分泌运动因子 (ATX) 的活性，此前报道称 ATX 是 HCV 相关肿瘤发生的一个促成因素。这表明IRF5可能作为HCV发病机制中的负限制因子。这些令人信服的证据支持 IRF5 在 HCV 复制和发病机制中的肿瘤抑制作用。拟议的研究将描述 HCV 感染期间 IRF5 调节的分子机制，并解决其调节和信号传导在 HCV 发病机制中的功能影响。这些研究的结果将确定对抗慢性丙型肝炎病毒感染的新分子靶点。