Mechanisms of Liver Inflammation

肝脏炎症的机制

基本信息

批准号：
8538971
负责人：
Harmeet Malhi
金额：
$ 14.6万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538971
关键词：
Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Apoptosis Binding Proteins Biological Assay Biology Boxing CCAAT-Enhancer-Binding Proteins Cartoons Cell Death Chemicals Clinical Data Development Disease Down-Regulation Endoplasmic Reticulum Fatty Liver Funding Goals Health Hepatic Homologous Protein Immune response Immunology In Vitro Individual Inflammation Inflammatory Inositol Interleukin-1 Interleukin-1 beta K-Series Research Career Programs Knockout Mice Lead Link Liver MCL1 protein Macrophage Activation Mediating Mediator of activation protein Mentors Molecular Genetics Monocyte Chemoattractant Protein-1 Natural Immunity Nonesterified Fatty Acids Obesity Organ Palmitic Acids Pathway interactions Plasma Proteins Regulation Research Rodent Rodent Model Role Scientist Signal Transduction Steatohepatitis Testing Therapeutic Intervention Training Transcriptional Activation Transcriptional Regulation Up-Regulation base career cytokine endoplasmic reticulum stress in vitro Model in vivo in vivo Model insight liver inflammation macrophage mouse model nonalcoholic steatohepatitis novel therapeutic intervention research study response

Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Apoptosis Binding Proteins Biological Assay Biology Boxing CCAAT-Enhancer-Binding Proteins Cartoons Cell Death Chemicals Clinical Data Development Disease Down-Regulation Endoplasmic Reticulum Fatty Liver Funding Goals Health Hepatic Homologous Protein Immune response Immunology In Vitro Individual Inflammation Inflammatory Inositol Interleukin-1 Interleukin-1 beta K-Series Research Career Programs Knockout Mice Lead Link Liver MCL1 protein Macrophage Activation Mediating Mediator of activation protein Mentors Molecular Genetics Monocyte Chemoattractant Protein-1 Natural Immunity Nonesterified Fatty Acids Obesity Organ Palmitic Acids Pathway interactions Plasma Proteins Regulation Research Rodent Rodent Model Role Scientist Signal Transduction Steatohepatitis Testing Therapeutic Intervention Training Transcriptional Activation Transcriptional Regulation Up-Regulation base career cytokine endoplasmic reticulum stress in vitro Model in vivo in vivo Model insight liver inflammation macrophage mouse model nonalcoholic steatohepatitis novel therapeutic intervention research study response

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项目摘要

DESCRIPTION (provided by applicant): My long term career objective is to define the mechanisms of liver inflammation in nonalcoholic steatohepatitis. The current proposal focuses on the dichotomous role of two of the three known branches of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) in the regulation of macrophage biology in NASH. In preliminary experiments we have observed that macrophages are activated upon treatment with palmitic acid (PA); we have termed this phenomenon lipoactivation. Lipoactivated macrophages undergo ER stress, and also cell death, termed lipoapoptosis. We have observed macrophage accumulation in a mouse model of NASH along with elevated PA levels. Our preliminary observations have led to the central hypothesis that the UPR regulates either lipoactivation or lipoapoptosis in hepatic macrophages thereby instigating or mitigating inflammation, respectively, in steatohepatitis. Therefore, the goals of this proposal are to understand: i) how the Inositol Requiring Protein-1 alpha (IRE1¿)/ X-box binding protein (XBP-1) branch of the UPR increases the proinflammatory milieu in the liver by enhancing macrophage activation and cytokine secretion via targeting the cytokines monocyte chemotactic protein-1 (MCP-1) and interleukin-1beta (IL-1¿), and ii) how the CHOP branch of the UPR increases the antiinflammatory milieu in the liver by enhancing macrophage apoptosis by decreasing the antiapoptotic protein Mcl-1 and increasing the proapoptotic protein Bim. The proposed experiments will employ complementary in vitro and in vivo models of lipotoxicity and NASH, respectively; and chemical, pharmacological, molecular and genetic approaches to address the specific aims to test the hypotheses that: i) The UPR determines macrophage recruitment and activation via IRE1¿/XBP-1 signalling, ii) ER stress via CHOP promotes macrophage apoptosis, and iii) The UPR regulates hepatic inflammation in NASH. To address these hypotheses the applicant has become adept at macrophage isolation, assays of cytokine secretion, transcriptional regulation, and in vivo rodent models of conditional deletion of IRE1¿ or CHOP. With funding through this K08 Mentored Clinical Scientist Research Career Development Award the applicant will pursue additional training in macrophage biology and Innate Immunology to develop expertise in these key regulators of hepatic inflammation. The applicant has established a network consisting of Dr. Gregory J. Gores as her primary mentor, Dr. Peter J. Wettstein as the Immunology collaborator, and Dr. Randal J. Kaufman as the UPR collaborator. Our results will yield mechanistic insights into regulation of macrophage lipoactivation and lipoapoptosis by individual UPR components, thus identifying potential molecules that can be targeted by therapeutic interventions.

描述（由适用提供）：我的长期职业目标是定义非酒精性脂肪性肝炎中肝炎的机制。当前的建议着重于内质网（ER）应激激活的未折叠蛋白反应（UPR）在NASH巨噬细胞生物学调节中的三个已知分支（ER）应激激活的蛋白质反应（UPR）的二分法作用。在初步实验中，我们观察到用棕榈酸（PA）治疗后，巨噬细胞被激活。我们称这种现象脂肪激活。脂肪活化的巨噬细胞经历了ER应激，也称为细胞死亡，称为脂肪凋亡。我们已经观察到在NASH小鼠模型中巨噬细胞的积累以及PA水平升高。我们的初步观察结果导致了一个中心假设，即UPR在肝巨噬细胞中调节脂肪激活或脂肪凋亡，从而分别在脂肪性肝炎中煽动或减轻感染。 Therefore, the goals of this proposal are to understand: i) how the Inositol Requiring Protein-1 alpha (IRE1¿ )/ X-box binding protein (XBP-1) branch of the UPR increases the proinflammatory milieu in the liver by enhancing macrophage activation and cytokine secretion via targeting the cytokines monocyte chemotactic protein-1 (MCP-1) and interleukin-1beta （IL-1？）和ii）UPR的CHOP分支如何通过减少抗凋亡蛋白MCL-1并增加促凋亡蛋白BIM来增强巨噬细胞凋亡来增加肝脏中的抗炎环境。所提出的实验将分别在体外和体内脂肪毒性和NASH的体内模型。 and chemical, pharmaceutical, molecular and genetic approaches to address the specific aims to test the hypotheses that: i) The UPR determines macrophage recruitment and activation via IRE1¿ /XBP-1 signalling, ii) ER stress via CHOP promotes macrophage apoptosis, and iii) The UPR regulates hepatitic inflammation in NASH.为了解决这些假设，适用的已适用于巨噬细胞隔离，细胞因子分泌的测定，转录调控以及在IRE1或CHOP的条件缺失的体内啮齿动物模型。通过这项K08指导的临床科学家研究职业发展奖的资金，该应用程序将在巨噬细胞生物学和先天免疫学方面进行其他培训，以在这些关键的肝炎炎症调节剂中发展专业知识。该应用程序已经建立了一个由Gregory J. Gores博士组成的网络，作为她的主要心态，Peter J. Wettstein博士为免疫学合作者，Randal J. Kaufman博士为UPR合作者。我们的结果将产生机械洞察，以调节单个UPR成分对巨噬细胞脂肪激活和脂肪凋亡的调节，从而鉴定出可以通过治疗性干预措施靶向的潜在分子。