Racial Differences in IFN Transcriptional Response

描述(申请人提供)：慢性丙型肝炎病毒(丙型肝炎病毒)是美国最流行的肝脏疾病之一。它与进行性肝纤维化、肝硬变和肝细胞癌风险增加有关。大约有240万美国人患有慢性丙型肝炎，非裔美国人的感染率(3.2%)高于高加索人口(1.5%)。令人痛心的是，丙型肝炎相关性肝硬变的死亡率和丙型肝炎引起的肝细胞癌的发病率似乎在增加，预计这些增加将不成比例地影响非裔美国人。与高加索人、墨西哥裔美国人和亚洲人相比，非洲裔美国人患者对基于α干扰素(干扰素)的治疗的应答率较低，这一事实放大了这一威胁。非裔美国人对抗病毒治疗相对缺乏反应的原因尚不清楚。干扰素治疗与血浆或血清中存在的病毒数量的双相性下降有关。最初的下降(阶段1)的特征是血清丙型肝炎病毒RNA水平在最初的24小时内迅速下降，随后在48小时后更缓慢地下降(阶段2)。通过数学模型的分析表明，干扰素-()的急性作用是由于阻止病毒粒子从肝脏产生或释放的抗病毒活性，而较慢的、后来的下降是由于免疫清除肝脏内的受感染细胞。然而，干扰素-()的实际“抗病毒”机制仍然不确定，而且由于其免疫调节作用，不能排除干扰素-()在增强从血清中清除病毒方面的重要作用。这项建议试图了解种族和宿主遗传因素在决定丙型肝炎病毒感染中干扰素反应方面的作用。简而言之，我们的假设是：(1)与高加索人相比，非裔美国人血清和肝脏中丙型肝炎病毒下降的速度将较慢，(2)病毒动力学上的差异反映了高加索人和非裔美国人在干扰素诱导的肝内和/或淋巴细胞基因表达上的差异，以及(3)分析早期病毒学应答者和无应答者对干扰素的转录反应的差异以及对复制子系统中丙型肝炎病毒RNA复制的特异性干扰素刺激基因(ISGs)的体外评估将有助于更好地理解参与抑制丙型肝炎病毒复制和诱导治疗的持续病毒学应答的宿主途径

DESCRIPTION (provided by the applicant): Chronic hepatitis C virus (HCV) is one of the most prevalent diseases of the liver in the United States. It is associated with progressive hepatic fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. Approximately 2.4 million Americans have chronic hepatitis C infection and the rate is higher among the African Americans (3.2%) than among the Caucasian population (1.5%). Distressingly, the mortality rates for hepatitis C-related cirrhosis and the incidence of hepatocellular carcinoma due to HCV appear to be increasing, and these increases are expected to disproportionably affect African Americans. This threat is magnified by the fact that African American patients have a lower rate of response to alpha interferon (IFN() based therapy compared to Caucasian, Mexican American and Asian patients. The reasons for the relative lack of response to antiviral therapy among African Americans are not clear. Therapy with IFN-( is associated with a Diphasic decline in the quantity of virus present in plasma or serum. The initial decline (phase 1) is characterized by a rapid decrease in serum HCV RNA levels in the first 24 hours and it is followed by a much more gradual decline by 48 hours onward (phase 2). Analysis by a mathematical model suggests that the acute effect of IFN-( is due to an antiviral activity that blocks virion production or release from the liver, while the slower, later decline is due to the immune removal of infected cells within the liver. However, the actual "antiviral" mechanisms of IFN-( remain uncertain and an important role for enhanced clearance of virus from the serum due to the immunomodulatory actions of IFN-( cannot be excluded. This proposal seeks to understand the role of racial and host genetic factors in determining interferon response in HCV infection. Briefly stated, our hypotheses are: (1) that the rates of the HCV decline in serum and liver after IFN-( will be slower among African Americans compared to Caucasians, (2) that this difference in viral kinetics reflects differences in IFN-( induced intrahepatic and/or lymphocytic gene expression among Caucasians and African Americans, and (3) that an analysis of differences in the transcriptional responses to IFN-( and the in vitro evaluation of specific Interferon stimulated genes (ISGs) on HCV RNA replication in the replicon system between early virological responders and non-responders will lead to a better understanding of host pathways involved in the suppression of hepatitis C virus replication and the induction of a sustained virological response to therapy