Hepatocarcinogenesis Secondary to Hepatitis C

继发于丙型肝炎的肝癌发生

• 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
• 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' 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

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，常常导致肝硬化和癌症。在美国，每年有 10,000 至 20,000 人死于慢性 HCV 感染。这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肝细胞癌的主要原因。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IFN-a和利巴韦林的联合疗法，但只有一半的患者能够通过这种疗法摆脱病毒感染。 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，并开发替代抗病毒策略来抑制 HCV 复制。在过去几年中，我们的研究产生了以下证据：（i）。我们开发了干扰素抗性复制子细胞系，并确定 Jak-Stat 信号通路的缺陷可导致 ISRE 启动子（IFN 启动子）低水平激活和干扰素抗性表型。 (二).我们已发表的数据显示 IFN-a、IFN-¿ 和 IFN-?每种都抑制 HCV 复制。干扰素的这种抑制作用是在核糖体加载到病毒所使用的 5'UTR 序列的水平上通过内部核糖体进入位点 (IRES) 依赖性机制翻译其基因组。 （三）。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，控制干扰素诱导基因转录的 Jak-Stat 信号分子的表达在肝脏中受感染的肝细胞之间存在差异。 Jak-Stat 信号传导缺陷的肝细胞在 IRES 翻译水平上逃避干扰素作用，导致病毒长期持续复制。我们提出，通过使用可生物降解的聚合物将 siRNA-74 封装到纳米颗粒中，可以有效地将 siRNA 递送至肝细胞，并可能为对干扰素无反应的慢性 HCV 患者提供一种新的治疗策略。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，我们将研究慢性 HCV 感染人类的​​肝脏对 IFN-α 的抵抗力。在具体目标2中，我们将研究IFN-α对抗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。如果这些实验成功，那么将加深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。这项研究可能会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。本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，就有可能开发出治疗慢性丙型肝炎病毒感染并预防肝癌的方法。