Determinants of Liver Injury in Chronic Hepatitis C Virus Infection

慢性丙型肝炎病毒感染肝损伤的决定因素

• 批准号: 7575792
• 负责人: DETLEF SCHUPPAN
• 金额: $ 55.81万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-11-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575792
• 关键词: Determinants; Liver; Injury; Chronic; Hepatitis

DESCRIPTION (provided by applicant): The majority of persons acutely infected with hepatitis C virus (HCV) will develop chronic infection, but not all subjects go on to develop the complications of chronic infection such as hepatic fibrosis or steatosis. Current antiviral treatments are neither effective nor available for most persons with chronic HCV infection, and thus chronic infection remains a significant health problem. The natural history of HCV liver disease combined with the epidemiology of this infection has resulted in an increasing prevalence of persons with chronic HCV, and rising rates of hepatic decomposition and hepatocellular carcinoma. However, our understanding of the host and viral determinants of liver disease progression are poorly understood. This program project will address the determinants of liver injury in chronic HCV infection, using cohorts with rapid disease progression and controls to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. This will be accomplished in three integrated projects: The first Project will test the hypothesis that failure of the CD4 response results in an inappropriate CD8+ cytotoxic T lymphocyte (CTL) and natural killer T (NKT) response that serves to drive fibrosis and viral evolution. The second Project will characterize the role of oxidative stress in chronic HCV and the mechanisms of hepatic steatosis. The third Project will determine which viral and host factors drive hepatic stellate cell activation as a key step in fibrosis. The projects will be supported by a clinical core, which will maintain a repository of clinical samples derived from cohorts with rapid progression (transplant, HIV/HCV co-infection and Schistosoma mansoni co-infection) as well as more slowly progressive disease. This joint use of common clinical material will facilitate maximal integration of results. Through this unique cooperative approach, we will determine which viral and host factors contribute to fibrosis, the major complication of chronic HCV infection, which might suggest new therapeutic strategies to prevent liver disease progression.

描述（由申请人提供）：大多数急性感染丙型肝炎病毒（HCV）的人会发展出慢性感染，但并非所有受试者继续发展出慢性感染的并发症，例如肝纤维化或脂肪变性。 当前的抗病毒治疗既不有效，也不适用于大多数慢性HCV感染的人，因此慢性感染仍然是一个重大的健康问题。 HCV肝病的自然历史与这种感染的流行病学相结合，导致患有慢性HCV患者的患病率越来越多，肝分解和肝细胞癌的发生率上升。但是，我们对肝病进展的宿主和病毒决定因素的理解知之甚少。该计划项目将使用具有快速疾病进展和对照的同类群体来解决慢性HCV感染中肝损伤的决定因素，以更好地理解将HCV的相对良性疗程与肝硬化的相对良性过程区分开的因素。这将在三个综合项目中完成：第一个项目将检验以下假设：CD4响应的失败导致CD8+细胞毒性T淋巴细胞（CTL）和天然杀伤T（NKT）反应的不适当，这有助于驱动纤维化和病毒进化。 第二个项目将表征氧化应激在慢性HCV中的作用和肝脂肪变性的机制。第三个项目将确定哪种病毒和宿主因子将肝星状细胞激活作为纤维化的关键步骤。这些项目将得到临床核心的支持，该核心将维持临床样本的存储库，这些临床样品源自具有快速进展的同类群体（移植，HIV/HCV共同感染和曼森共同感染），以及更缓慢的渐进疾病。这种共同临床材料的联合使用将促进结果的最大整合。通过这种独特的合作方法，我们将确定哪些病毒和宿主因素有助于纤维化，这是慢性HCV感染的主要并发症，这可能提出了预防肝病进展的新治疗策略。

项目成果

Anti-fibrotic therapy: Lost in translation?

• DOI: 10.1016/s0168-8278(12)60008-7
• 发表时间: 2012-01-01
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Schuppan, Detlef;Pinzani, Massimo
• 通讯作者: Pinzani, Massimo

Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis.

• DOI: 10.1002/hep.23144
• 发表时间: 2009-11
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Patsenker, Eleonora;Popov, Yury;Stickel, Felix;Schneider, Vreni;Ledermann, Monika;Saegesser, Hans;Niedobitek, Gerald;Goodman, Simon L.;Schuppan, Detlef
• 通讯作者: Schuppan, Detlef

Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.

• DOI: 10.1002/hep.27936
• 发表时间: 2015-10
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Jiménez Calvente C;Sehgal A;Popov Y;Kim YO;Zevallos V;Sahin U;Diken M;Schuppan D
• 通讯作者: Schuppan D

IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.

• DOI: 10.1002/hep.23912
• 发表时间: 2010-12
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Urban, Thomas J.;Thompson, Alexander J.;Bradrick, Shelton S.;Fellay, Jacques;Schuppan, Detlef;Cronin, Kenneth D.;Hong, Linda;McKenzie, Alexander;Patel, Keyur;Shianna, Kevin V.;McHutchison, John G.;Goldstein, David B.;Afdhal, Nezam
• 通讯作者: Afdhal, Nezam