HEPATITIS C AND CRYOGLOBULINEMIA

描述：有两个共同赞助者(导师)：Jack T.Stapleton，M.D.， 是一位医学副教授，也是 爱荷华大学艾滋病临床试验小组的分支机构。道格拉斯R。 拉布里克，医学博士，内科教授，肝脏服务主任 (UI)，爱荷华市退伍军人医院胃肠病-肝病科主任。 丙型肝炎病毒(丙型肝炎病毒)是一种引起慢性肝炎的小RNA病毒 在大多数患者中。特发性混合性冷球蛋白血症(EMC) 作为慢性丙型肝炎病毒感染的主要肝外并发症出现 导致各种系统性疾病，如关节炎、脉管炎和 肾小球肾炎。EMC的特点是看起来冷而不溶 含有类风湿因子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 然而，病毒在EMC病因中的作用尚不清楚。 现有证据表明，传染性病毒粒子可能与 冷冻球蛋白并导致EMC引起的全身性疾病。使用 亲和捕获聚合酶链式反应新技术的建立 同事们最近证明，丙型肝炎病毒可以结合免疫球蛋白Fc。 碎片。病毒与Fc片段或非中和抗体的结合 可能是丙型肝炎病毒感染发病机制和自然病程中的关键一步。 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学 将确定病毒包膜上发生这种情况的位置(S)。vbl.使用 候选人将确定的细菌和真核细胞表达载体 与Fc片段特异相互作用的包膜蛋白序列。 在患有和不患有冷球蛋白血症的患者中，候选人将确定 针对临床状态和意愿的丙型肝炎病毒包膜蛋白序列 描述这些部位的抗原性和参与 冷沉淀形成。最后，体外细胞结合研究 病毒-Fc复合体和纯化的冷沉淀物将决定 这些免疫复合体在丙型肝炎病毒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 并确定治疗丙型肝炎的进一步治疗方案 丙型肝炎引起的慢性肝炎和冷球蛋白血症。

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.