Role of Pellino1 in liver inflammation

描述（申请人提供）：肝脏病毒感染是常见的，影响生活质量和预期寿命。据估计，全世界有超过20亿人感染乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）。这两种病毒都能引起慢性肝脏炎症、组织损伤和肝细胞癌。每年约有65万人死于HBV或HCV感染。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。白细胞介素-1 （IL-1）是一种多效性细胞因子，可引发许多针对感染和组织损伤的免疫反应，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刺激细胞反应，导致某些mrna的稳定和AP-1、NF-kB和STAT3等因子介导的转录增加。这些信号通路由病原体识别toll样受体共享，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制动，IRAK1调节不足可能在慢性炎症中发挥重要作用。Pellino蛋白Pellino1和Pellino2是一类参与Toll/IL-1信号转导的新蛋白。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。我们之前的研究表明，Pellino蛋白参与IL-1信号传导，并与包括IRAK1在内的几种信号分子相互作用。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，并且在HBV或HCV感染患者的肝组织中Pellino1的表达下调。这种表达模式似乎是肝脏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的能力降低。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基因敲除小鼠菌株将被表征和评估，作为一种模型，我们的假设可以被检验和肝脏疾病的研究。Pellino1在人类HBV和HCV感染中的表达将被确定。通过siRNA介导的Pellino1 mRNA的敲低，Pellino1依赖性基因在人肝细胞中的表达将使用全基因组微阵列表达谱来定义。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。公共卫生相关性：肝脏病毒感染引起肝脏炎症（肝炎）和癌症是常见的，并影响生活质量和预期寿命。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途径，并利用这些知识开发乙型肝炎和丙型肝炎的新疗法，并探索参与调节肝细胞中促炎白细胞介素-1信号转导的分子机制。对肝脏炎症及其相关分子途径的进一步了解可能有助于开发肝炎和肝癌的新疗法。

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.