Role of Pellino1 in liver inflammation

Pellino1 在肝脏炎症中的作用

• 批准号: 7862491
• 负责人: LISELOTTE E JENSEN
• 金额: $ 18.56万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862491
• 关键词: Acute-Phase Reaction; Affect; Animal Model; Area; Cell Death; Cells; Chronic; Chronic Disease; Cirrhosis; Data; Development; Disease; Disease Outcome; Down-Regulation; Expectancy; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Polymorphism; Genetic Transcription; Goals; Hepatitis; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; IL8 gene; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Knockout Mice; Knowledge; Lead; Leukocytes; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Messenger RNA; Modeling; Modification; Molecular; Molecular Profiling; Mouse Strains; NF-kappa B; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Plasma; Play; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Proteins; Public Health; Quality of life; RNA Interference; Regulation; Research; Research Personnel; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Small Interfering RNA; Staging; Testing; Time; Tissues; Toll-Like Receptor 1; Toll-like receptors; Transcription Factor AP-1; Viral; Virus; Virus Diseases; cytokine; genome-wide; hepatoma cell; human IRAK1 protein; improved; interest; interleukin-1 receptor-associated kinase; liver infection; mouse model; new therapeutic target; novel; pathogen; prevent; public health relevance; response; tissue culture

DESCRIPTION (provided by applicant): Viral infections of the liver are common and affect life quality and expectancy. It is estimated that over 2 billion people worldwide are infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). Both viruses can cause chronic inflammation of the liver, tissue damage and hepatocellular carcinoma. Approximately 650,000 people die each year due to infections with HBV or HCV. Our long-term goals are to elucidate molecular mechanisms regulating inflammation, identify defective pathways in diseases and use this knowledge to develop novel therapies. Interleukin-1 (IL-1) is a pleiotropic cytokine that initiates many of the immunological responses to infections and tissue damage, including local inflammation and systemic acute phase responses. IL-1 stimulates cellular responses through activation of intracellular signaling pathways leading to stabilization of certain mRNAs and increased transcription mediated by factors such as AP-1, NF-kB and STAT3. The signaling pathways are shared by the pathogen recognizing Toll-like receptors and involve IL-1 receptor associated kinase-1 (IRAK1). Rapid degradation of IRAK1 following cell stimulation appears to provide a molecular brake on inflammation and inadequately regulated IRAK1 may play an important role in chronic inflammation. The Pellino proteins Pellino1 and Pellino2 represent a novel group of proteins, which appear to be involved in Toll/IL-1 signal transduction. However, their functions are largely unknown. We have previously identified a novel Pellino protein, Pellino3. Our previous studies have demonstrated that Pellino proteins are involved in IL-1 signaling and interact with several signaling molecules, including IRAK1. New data suggest that Pellino proteins regulate post-transcriptional modification and activity of IRAK1. Preliminary analyses also indicate that Pellino1 is the predominant form in hepatocytes and expression of Pellino1 is down-regulated in liver tissue from patients infected with HBV or HCV. This expression pattern appears to be specific to liver tissue and viral infections of the liver. Hepatocytes with reduced Pellino1 levels have a diminished capacity to produce IL-8. We hypothesize that down-regulation of Pellino1 facilitates diminished inflammatory responses of hepatocytes. A novel Pellino1 knockout mouse strain will be characterized and evaluated as a model in which our hypothesis can be tested and liver disease studied. Expression of Pellino1 during human HBV and HCV infections will be determined. Through siRNA mediated knockdown of Pellino1 mRNA Pellino1 dependent gene expression in human hepatocytes will be defined using genomewide microarray expression profiling. These studies will significantly improve our understanding of the involvement of Pellino1 in liver inflammation. The project will further set the stage for future exploration of the role of IL-1, Pellino1 and hepatocytes in liver disease and disease outcomes. PUBLIC HEALTH RELEVANCE: Viral infections of the liver causing liver inflammation (hepatitis) and cancer are common and affect life quality and expectancy. This project will elucidate molecular mechanisms regulating inflammation, specifically identifying defective pathways in diseases and using this knowledge to develop new therapies for both hepatitis B and hepatitis C and explore molecular mechanisms involved in regulating pro-inflammatory interleukin-1 signal transduction in liver cells. An improved understanding of liver inflammation and the associated molecular pathways may facilitate the development of novel therapies for hepatitis and liver cancer.

描述(申请人提供)：肝脏的病毒感染很常见，影响生活质量和预期。据估计，全球有超过20亿人感染了乙肝病毒或丙型肝炎病毒。这两种病毒都会导致肝脏慢性炎症、组织损伤和肝细胞癌。每年约有65万人死于感染乙肝病毒或丙型肝炎病毒。我们的长期目标是阐明调节炎症的分子机制，识别疾病中的缺陷途径，并利用这些知识开发新的治疗方法。白介素1(IL-1)是一种多效性细胞因子，可启动对感染和组织损伤的许多免疫反应，包括局部炎症和全身急性期反应。IL-1通过激活细胞内信号通路来刺激细胞反应，导致某些mRNAs的稳定，并在AP-1、NF-kB和STAT3等因子的介导下增加转录。这些信号通路由识别Toll样受体的病原体共享，并涉及IL-1受体相关激酶-1(IRAK1)。细胞刺激后IRAK1的快速降解似乎为炎症提供了分子刹车，调节不充分的IRAK1可能在慢性炎症中发挥重要作用。Pellino蛋白Pellino1和Pellino2代表了一组新的蛋白质，它们似乎参与了Toll/IL-1信号转导。然而，它们的功能在很大程度上是未知的。我们之前已经鉴定出一种新的Pellino蛋白，Pellino3。我们之前的研究已经证明，Pellino蛋白参与了IL-1信号转导，并与包括IRAK1在内的几个信号分子相互作用。新的数据表明，Pellino蛋白调节IRAK1的转录后修饰和活性。初步分析还表明，Pellino1是肝细胞中的主要形式，在感染乙肝病毒或丙型肝炎患者的肝组织中，Pellino1的表达下调。这种表达模式似乎是肝组织和肝脏病毒感染所特有的。Pellino1水平降低的肝细胞产生IL-8的能力减弱。我们假设Pellino1的下调有助于减轻肝细胞的炎症反应。一种新的Pellino1基因敲除小鼠品系将被描述和评估为一个模型，在其中我们的假设可以被验证，肝脏疾病可以被研究。将测定Pellino1在人类感染乙肝病毒和丙型肝炎病毒过程中的表达。通过siRNA介导的Pellino1基因表达下调，Pellino1依赖的基因在人肝细胞中的表达将通过全基因组微阵列表达谱来确定。这些研究将显著提高我们对Pellino1参与肝脏炎症的理解。该项目将进一步为未来探索IL-1、Pellino1和肝细胞在肝脏疾病和疾病结局中的作用奠定基础。与公共卫生相关：引起肝脏炎症(肝炎)和癌症的肝脏病毒感染很常见，影响生活质量和预期。该项目将阐明调节炎症的分子机制，特别是识别疾病中的缺陷通路，并利用这些知识开发治疗乙肝和丙型肝炎的新疗法，并探索参与调节肝细胞中促炎症的白介素1信号转导的分子机制。对肝脏炎症和相关分子途径的了解的提高可能有助于开发治疗肝炎和肝癌的新疗法。