The Role of IL-17 in Alcoholic Liver Disease and Cancer

IL-17 在酒精性肝病和癌症中的作用

• 批准号: 8913875
• 负责人: Michael Karin
• 金额: $ 34.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913875
• 关键词: Affect; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Animal Model; Attenuated; CXCL1 gene; Cells; Chemotactic Factors; Chronic; Cirrhosis; Cytochromes; Data; Development; Diethylnitrosamine; Disease Pathway; Disease Progression; Enzymes; Ethanol; Ethanol Metabolism; Exhibits; Fibrosis; Genes; Genetic study; Goals; Health; Healthcare; Hepatic Stellate Cell; Hepatocyte; Incidence; Inflammatory; Injury; Interleukin-17; Interleukin-18; Interleukin-6; Knockout Mice; Kupffer Cells; Lipid Peroxidation; Liver; Liver Cirrhosis; Liver Fibrosis; Macrophage Activation; Malignant neoplasm of liver; Measures; Mediating; Modeling; Molecular Profiling; Mus; Myofibroblast; Neutrophil Infiltration; Oxidoreductase; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Primary carcinoma of the liver cells; Production; Reactive Oxygen Species; Regulation; Role; STAT3 gene; Signal Pathway; Signal Transduction; Source; Staging; Steatohepatitis; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Tumor Necrosis Factor-alpha; Up-Regulation; Wild Type Mouse; alcohol response; attenuation; base; care burden; cell type; cytokine; drinking water; feeding; improved; inhibitor/antagonist; injured; insight; interleukin-23; liver cell proliferation; mouse model; neutrophil; novel strategies; pre-clinical; problem drinker; receptor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) progresses from a normal liver, to alcoholic steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Despite of intensive studies, the pathogenesis of ALD is poorly understood due to the lack of animal models which mimic the stages of ALD progression. Furthermore, the role of IL-17 in ALD has not been evaluated. We have recently demonstrated that IL-17 signaling plays a critical role in development of liver fibrosis and cancer. Based on our preliminary data, IL-17 signaling also required for ALD, and mice devoid of IL-17 signaling develop less steatohepatitis and fibrosis. Here we propose to further explore the role of IL-17 in ALD, using an improved model of ALD in mice, which was developed as a result of a collaborative effort of Drs. Karin, Gao, Tsukamoto and Kisseleva. This model most closely reproduces the stages of ALD and reflects physiological ALD progression from steatohepatitis to alcohol-induced liver fibrosis and HCC in patients. Our central hypothesis is that IL-17 exacerbates progression of ALD from steatohepatitis to fibrosis and HCC. The goal of the study is to determine if the strategy of blocking IL-17 will have a therapeutic effect on ALD. The role of IL-17 signaling in ALD, and pathways of IL-17 regulation will be tested in this study using IL-17-/-, IL-17RA-/-, and several cell-specific knockout mice to determine the role of IL- 17 signaling 1) chronic-binge model that mimics early stages of steatohepatitis (AIM 1), 2) intragastric ethanol feeding model that mimics alcoholic steatohepatitis and fibrosis (AIM 2), and 3) diethylnitrosamine (DEN)+alcohol model that mimics alcoholic liver cancer (AIM 3). Specifically, these models will allow us to dissect specific IL-17 functions at different stages of ALD. Thus, for each model, 1) development of alcohol- induced liver injury will be determined by measuring alcohol-metabolizing enzymes dehydrogenase (ADH), cytochrome, P4502E1 (CYP2E1), expression of adipogenic genes (PPARγ, PPARα, CEBP1), lipid peroxidation, ROS production. 2) The role of IL-17 in recruitment of inflammatory cells, Kupffer cells/macrophage activation will be determined. 3) The cellular sources of IL-17 will be identified. 4) The IL-17 target cells that critically mediate ALD progression will be determined, specific cell types will be isolated and ex vivo analyzed. 5) We will generate conditional IL-17RA-/- knockout mice in Kupffer cells, hepatocytes and Hepatic Stellate Cells (HSCs) to study their contribution to ALD. 6) The global cytokine expression profile will determined for each type of knockout mice. 7) The regulatory role of IL-23, IL-25 and IL-27 cytokines in IL-17 by Th17 cells (or other IL-17 producing cells) will be determined. These unique genetic studies will provide an insight into usefulness of IL-17 inhibitors as a novel approach to treat ALD in patients.

描述（由适用提供）：酒精性肝病（ALD）从正常肝脏发展到酒精性脂肪性肝炎，纤维化和肝细胞癌（HCC）。尽管进行了深入研究，但由于缺乏模仿ALD进展阶段的动物模型，ALD的发病机理却很少理解。此外，尚未评估IL-17在ALD中的作用。我们最近证明，IL-17信号在肝纤维化和癌症的发展中起着至关重要的作用。根据我们的初步数据，ALD也需要IL-17信号传导，而没有IL-17信号的小鼠会产生较少的脂肪性肝炎和纤维化。在这里，我们建议在小鼠中使用改进的ALD模型进一步探索IL-17在ALD中的作用，该模型是由于DRS的协作努力而开发的。 Karin，Gao，Tsukamoto和Kisseleva。该模型最紧密地再现了ALD的阶段，并反映了患者的身体ALD从脂肪性肝炎到酒精诱导的肝纤维化和HCC的身体进展。我们的中心假设是IL-17加剧了从脂肪性肝炎到纤维化和HCC的ALD的发展。该研究的目的是确定阻止IL-17的策略是否会对ALD产生治疗作用。 IL-17信号在ALD中的作用以及IL-17调控的途径将在本研究中使用IL-17 - / - ，IL-17RA - / - 以及几只细胞特异性的基因敲除小鼠到 确定IL-17信号的作用1）模仿脂肪性肝炎的早期阶段的慢性 - 屈服模型（AIM 1），2）胃内乙醇乙醇进食模型，以模拟酒精性脂肪性肝炎和纤维化（AIM 2），以及3）二乙基硝基胺（DEN）+酒精模型（DEN）+酒精模型，该模型模仿酒精癌症（AIM）AIM癌症3。具体而言，这些模型将使我们能够在ALD的不同阶段剖析特定的IL-17功能。对于每个模型，1）通过测量酒精代谢酶脱氢酶（ADH），细胞色素，P4502E1（CYP2E1）的发育，将确定饮酒引起的肝损伤，PPARγ，PPARγ，PPARγ，PPARα，CEBP1，CEBP1），Lipid cebp1，lipid peroxidation，lipid peroxidation，Ros Rosepartion，Ros Ros Ros。 2）IL-17在炎症细胞募集中的作用，将确定库普弗细胞/巨噬细胞激活。 3）IL-17的细胞源将为4）将确定严重介导ALD进展的IL-17靶细胞，将分离出特定的细胞类型并进行离体分析。 5）我们将在库普弗细胞，肝细胞和肝星状细胞（HSC）中生成条件IL-17RA - / - 基因敲除小鼠，以研究其对ALD的贡献。 6）将针对每种类型的基因敲除小鼠确定全局细胞因子表达谱。 7）将确定IL-23，IL-25和IL-27细胞因子在IL-17中通过Th17细胞（或其他IL-17产生细胞）在IL-17中的调节作用。这些独特的遗传研究将洞悉IL-17抑制剂作为治疗患者ALD的新方法的有用性。