Determining the function of IRF5 tumor suppressor in HCV pathogenesis

 描述（由申请人提供）：摘要丙型肝炎病毒（HCV）感染是一种重要的人类血液传播病原体，是发生肝细胞癌（HCC）的最重要危险因素，HCC是全球主要的肝脏恶性肿瘤和癌症类型。85%的HCV感染会变成慢性，并伴有后遗症，包括纤维化、肝硬化和最终的HCC，HCC是一种高度恶性的肿瘤，目前诊断后的平均生存率不到1年。目前，没有针对HCV的预防性疫苗，尽管抗HCV疗法在过去两年中取得了进展，但由于不同方案在不同患者群体中的相对功效、导致患者不依从的不良药物作用、耐药变体的快速出现、获得护理和治疗成本，治疗成功受到限制。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，更好地了解调节HCV发病机制的病理生理学机制，以解决这一全球危机，并确定新的分子靶点是非常必要的。在本申请中，我们将讨论干扰素调节因子5（IRF5）在HCV发病机制中的作用。IRF5属于干扰素调节因子（IRF）家族的转录因子，其在病毒、IFN和DNA损伤诱导的信号传导途径中发挥关键作用。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现在与几种人类癌症有关。令人惊讶的是，其在HCV发病机制中的作用至今尚未被探索。虽然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著下调，并且IRF5过表达进一步抑制HCV翻译和复制。重要的是，我们提供了重要的证据，IRF5抑制癌基因自分泌运动因子（ATX）的活性，以前报道为HCV相关肿瘤发生的一个促成因素。提示IRF5可能是HCV致病过程中的一个负性限制因子。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。这些研究将阐明IRF5在HCV感染过程中调控的分子机制，并阐明其在HCV发病机制中的调节和信号传导的功能意义。这些研究的结果将确定新的分子靶点来对抗慢性HCV感染。

 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.