Hepatocarcinogenesis Secondary to Hepatitis C

继发于丙型肝炎的肝癌发生

基本信息

批准号：
7529066
负责人：
Srikanta Dash
金额：
$ 29.34万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529066
关键词：
5&apos Untranslated Regions Antiviral Agents Antiviral Response Cell Line Cells Cessation of life Chronic Chronic Hepatitis C Clinical Confusion Data Defect Development Endopeptidases Gene Expression Genes Genetic Transcription Genome Genomics Genotype Goals Grant Hepatic Hepatitis C Hepatitis C virus Hepatocarcinogenesis Hepatocyte Human Immunization Infection Inflammation Interferon-alpha Interferons Internal Ribosome Entry Site Lead Length Liver Liver Cirrhosis Malignant Neoplasms Malignant neoplasm of liver Maps Mediating Messenger RNA Methods MicroRNAs Patients Peptide Hydrolases Phenotype Play Primary carcinoma of the liver cells Primer Extension Principal Investigator Production Protein Kinase Public Health Publishing RNA Rate Replicon Reporting Research Research Proposals Resistance Resistance development Ribavirin Ribosomes Role Secondary to Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA System Testing Therapeutic Translating Translations Treatment Protocols United States Viral Viral Genome Virus Virus Diseases Virus Replication base biodegradable polymer density innovation interferon therapy liver transplantation nanoparticle novel therapeutics polylactic acid-polyglycolic acid copolymer prevent programs promoter research study resistance mechanism response viral RNA

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major public health problem with more than 170 millions people are currently infected. Most infections become chronic often leading to liver cirrhosis and cancer. In the United States 10,000 to 20,000 deaths a year are caused by chronic HCV infection. It is the most common cause of liver transplantation. It is now believed that long-standing chronic inflammation secondary to HCV infection is the main cause of hepatocellular carcinoma. The mechanisms underlying the development of long-lasting chronic inflammation and cancer are not well understood. Current therapy for chronic HCV infection, a combination of IFN-a and ribavirin, but only half of the patients can get rid of the virus infection by this regimen. The reasons why HCV infection leads to a high rate of chronic infection in human and often develops resistance to interferon therapy are not clear. The overall goals of this proposal are to understand the mechanisms of interferon action and resistance in chronic HCV infection, and develop alternative antiviral strategies to inhibit HCV replication. During the last couple of years our research has generated the following evidences: (i). We have developed interferon-resistant replicon cell lines and determined that a defect in the Jak-Stat signaling pathway can lead to low-level activation of ISRE promoter (IFN-promoter) and interferon resistance phenotypes. (ii). We have published data showing that IFN-a, IFN-¿ and IFN-? each inhibits HCV replication. This inhibitory effect of interferon is at the level of ribosome loading to the 5'UTR sequences used by the virus to translate its genome by an internal ribosome entry site (IRES) dependent mechanism. (iii). Recently, we have reported that small interfering RNA (siRNA) targeted to the IRES region that can inhibit translation of six different HCV genotypes. Based on these preliminary studies our hypothesis is that the expression of the Jak-Stat signaling molecules that control the transcription of interferon-inducible genes varies among infected hepatocytes in the liver. Hepatocytes with a defective Jak-Stat signaling escape interferon action at the level of IRES translation leading to chronic persistent virus replication. We propose that encapsulation of siRNA-74 into nanoparticles by the use of biodegradable polymers will efficiently deliver siRNA to the hepatocytes and may provide a novel therapeutic strategy for chronic HCV patients who are non-responders to interferon. To test our hypothesis we have developed three Specific Aims. In Specific Aim 1, we will investigate hepatic resistance to IFN-alpha in HCV chronically infected humans. In Specific Aim 2, we will investigate the antiviral mechanisms of IFN-alpha against hepatitis C virus. In Specific Aim 3, we will formulate biodegradable nanocapsules as a non-viral method to deliver siRNA to inhibit viral target of interferon to overcome mechanisms of resistance. If these experiments are successful then it will increase our understanding on the mechanisms of interferon action and resistance against chronic HCV. This research will potentially leads to an innovative therapeutic strategy for chronic hepatitis C patients not responding to interferon therapy. Public Health Relevance: Chronic hepatitis C virus infection is the major cause of liver cancer in the United States. This research proposal intends to develop intracellular immunization strategy to inhibit HCV. If these experiments are successful it can potentially lead to a therapy for chronic HCV infection and prevent liver cancer.

描述（由申请人提供）：丙型肝炎病毒 (HCV) 是一个主要的公共卫生问题，目前有超过 1.7 亿人受到感染，大多数感染会变成慢性，通常会导致美国 10,000 至 20,000 人死亡。慢性HCV感染是肝移植最常见的原因，目前认为HCV感染继发的长期慢性炎症是其主要原因。长期慢性炎症和癌症发展的机制尚不清楚，目前治疗慢性 HCV 感染的疗法是联合使用 IFN-a 和利巴韦林，但只有一半的患者可以摆脱病毒感染。 HCV 感染导致人类慢性感染率高且经常对干扰素治疗产生耐药性的原因尚不清楚。该提案的总体目标是了解干扰素在慢性 HCV 感染中的作用和耐药机制。，并开发替代方案在过去几年中，我们的研究产生了以下证据：（i）我们开发了抗干扰素复制子细胞系，并确定 Jak-Stat 信号通路的缺陷可能导致低水平。 -ISRE 启动子（IFN-启动子）的水平激活和干扰素抗性表型（ii）。干扰素的这种抑制作用是在病毒使用的核糖体加载水平上通过内部核糖体进入位点（IRES）依赖性机制来翻译其基因组的。最近，我们报道了靶向 IRES 区域的小干扰 RNA (siRNA)，可以抑制六种不同 HCV 基因型的翻译。基于这些初步研究，我们的假设是 Jak-Stat 信号分子的表达。控制受感染肝细胞中干扰素诱导基因转录的基因在肝脏中存在差异，具有缺陷的 Jak-Stat 信号转导在 IRES 翻译水平上逃避干扰素作用，导致慢性持续病毒复制。使用可生物降解聚合物的纳米颗粒将有效地将 siRNA 递送至肝细胞，并可能为对干扰素无反应的慢性 HCV 患者提供新的治疗策略。为了检验我们的假设，我们制定了三个具体目标。在具体目标 1 中，我们将研究 HCV 慢性感染人群的肝脏对 IFN-α 的抵抗力。在具体目标 2 中，我们将研究 IFN-α 对丙型肝炎病毒的抗病毒机制。在具体目标 3 中，我们将配制可生物降解的纳米胶囊作为一种非病毒方法来递送 siRNA，以抑制干扰素的病毒靶标，从而克服耐药机制。如果成功的话，它将增加我们对干扰素作用机制和对慢性丙型肝炎病毒抵抗力的了解，这项研究将有可能为对干扰素治疗无反应的慢性丙型肝炎患者带来创新的治疗策略。公共卫生相关性：慢性丙型肝炎病毒感染是美国肝癌的主要原因。该研究计划旨在开发抑制丙型肝炎病毒的细胞内免疫策略，如果这些实验成功，可能会导致慢性丙型肝炎病毒感染的治疗。并预防肝癌。