HEPATITIS C AND CRYOGLOBULINEMIA

描述：有两个共同发起人（导师）：杰克T。斯台普顿，医学博士， 是医学副教授和首席研究员 爱荷华州大学艾滋病临床试验小组。 道格拉斯河 拉布雷克，医学博士是教授，内科，主任，肝脏服务 (UI)爱荷华州市VA医院胃肠病学-肝病学主任。 丙型肝炎病毒（HCV）是一种引起慢性肝炎的小RNA病毒 在大多数患者中。 原发性混合型冷球蛋白血症（EMC） 作为慢性HCV感染的主要肝外并发症出现， 引起多种全身性疾病，如关节炎、血管炎， 肾小球肾炎 EMC的标志是冷不溶物的外观 具有流变因子（RF）的球蛋白和冷沉淀物。 冷沉淀物已被证明含有RF，抗丙型肝炎抗体 和HCV RNA，然而，病毒在EMC病因中的作用尚不清楚。 现有证据表明，感染性病毒体可能与 cryobacterulins和有助于由EMC引起的全身性疾病。 使用 一种新开发的亲和捕获PCR技术， 同事们最近发现HCV可以结合免疫球蛋白Fc， 片段 病毒与Fc片段或非中和抗体的结合 可能是HCV感染的发病机制和自然史中的关键步骤 和冷球蛋白血症。 在本申请中，候选人将进一步 表征病毒-Fc片段结合的动力学和化学计量， 将确定发生这种情况的病毒包膜上的位点。 使用 候选人将鉴定细菌和真核细胞表达载体 与Fc片段特异性相互作用的包膜蛋白序列。 在有和没有冷球蛋白血症的患者中，候选人将确定 HCV包膜蛋白序列特异于临床状态，并将 表征这些位点的抗原性和参与 冷沉淀形成。 最后，体外细胞结合研究， 病毒-Fc复合物和纯化的冷沉淀物将决定 这些免疫复合物在HCV靶细胞感染中的重要性。 基于 这些方法，候选人希望阐明细胞机制， HCV感染，并确定进一步的治疗选择， 慢性肝炎和由HCV引起的冷球蛋白血症。

DESCRIPTION: There are two co-sponsors (mentors): Jack T. Stapleton, M.D., is an associate professor of medicine and Principal Investigator of the University of Iowa Subunit of the AIDS Clinical Trials Group. Douglas R. LaBrecque, M.D. is Professor, Internal Medicine, Director, Liver Service (UI), and Chief, Gastroenterology-Hepatology, at the VA Hospital, Iowa City. Hepatitis C virus (HCV) is a small RNA virus that causes chronic hepatitis in a majority of patients. Essential mixed cryoglobulinemia (EMC) has emerged as a major extrahepatic complication of chronic HCV infection and causes a variety of systemic diseases such as arthritis, vasculitis, and glomerulonephritis. The hallmark of EMC is the appearance of cold insoluble globulins with Rheumatoid Factor (RF) and cryoprecipitates. Cryoprecipitates have been shown to contain RF, anti-hepatitis C antibodies and HCV RNA, however, the role of the virus in the cause of EMC is unclear. Available evidence suggests that infectious virions may associate with cryoglobulins and contribute to the systemic disease caused by EMC. Using a newly developed technique of affinity-capture PCR the candidate and his colleagues have recently shown that HCV can bind immunoglobulin Fc fragments. Binding of virus to Fc fragments or to non-neutralizing antibody may be a key step in the pathogenesis and natural history of HCV infection and cryoglobulinemia. In this application the candidate will further characterize the kinetics and stoichiometry of virus-Fc fragment biding and will determine the site (s) on the viral envelope where this occurs. Using bacterial and eukaryotic cell expression vectors the candidate will identify the envelope protein sequences that interact specifically with Fc fragment. In patients with and without cryoglobulinemia the candidate will determine HCV envelope protein sequences specific to the clinical state and will characterize these sites as to their antigenicity and participation in cryoprecipitate formation. Finally, in vitro cellular binding studies with virus-Fc complexes and purified cryoprecipitates will determine the importance of these immunocomplexes in HCV target cell infection. Based on these approaches, the candidate hopes to elucidate the cellular mechanisms of HCV infection and identify further therapeutic options for treatment of chronic hepatitis and cryoglobulinemia due to HCV.