IRAKM and Mincle in ALD

IRAKM 和 Mincle 在 ALD 中

基本信息

批准号：
8912063
负责人：
Xiaoxia Li
金额：
$ 43.81万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912063
关键词：
Affect Alcohol abuse Alcoholic Liver Diseases Alcohols American Animal Model BCL10 gene Biochemical C Type Lectin Receptors Cell Death Cessation of life Chronic Cirrhosis Complex Data Development Disease Progression Dose Ethanol Family Fibrosis Foundations Future Genes Genetic Goals Hepatic Hepatitis Hepatocyte IRAK1 gene IRAK2 gene IRAK4 gene Indium Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Intestines Kupffer Cells Lead Ligands Link Lipopolysaccharides Liver Liver Circulation MAP3K7 gene Mediating Molecular Morbidity - disease rate Mus Myeloid Cells Pathogenesis Pathway interactions Patients Permeability Phosphotransferases Post-Transcriptional Regulation Prevention Primary carcinoma of the liver cells Production Regulation Reporting Research Project Grants Role Signal Transduction Source Stimulus TNF gene Testing Therapeutic Therapeutic Intervention Time Translations Up-Regulation Work alcohol exposure base chemokine cytokine design endoplasmic reticulum stress extracellular feeding fibrogenesis human IRAK3 protein improved injured interest macrophage member mitochondrial dysfunction mortality mouse model pre-clinical preclinical study problem drinker public health relevance response response to injury sensor stellate cell toll-like receptor 4 upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a major source of alcohol-related morbidity and mortality. It is estimated that 10-15 percent of alcoholics develop fibrosis, cirrhosis and hepatocellular carcinoma. Inflammatory responses are critical contributors to disease progression. One important pathway to increased inflammation results from increased intestinal permeability and changes in bacterial microflora, resulting in activation of Toll-like receptor 4 (TLR4) on Kupffer cells. However, ethanol also directly injures hepatocytes; our preliminary data indicate that signals from injured hepatocytes are also critical to the activation of hepatic macrophages. The overall objective of this proposal is to investigate how TLR-dependent inflammatory responses, in combination with alcohol-induced hepatocellular injury, coordinately lead to pathogenesis of ALD. TLRs transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase (IRAK) family, including IRAK1, IRAK2, IRAKM and IRAK4. IRAK4, the upstream kinase, directly interacts with MyD88. While MyD88- IRAK4-IRAK1 mediates TAK1-dependent NFB activation, MyD88-IRAK4-IRAK2 is critical for post- transcriptional control. While IRAKM interacts with MyD88-IRAK4 to mediate a MEKK3-dependent second wave NFB activation, it interacts with IRAK2 to inhibit translation of cytokines and chemokines. Thus, IRAKM exerts an overall inhibitory effect on inflammatory responses. Surprisingly, we found IRAKM-deficient mice were protected from ethanol-induced liver injury. Array analysis led us to be interested in one particular TLR4-induced IRAKM-dependent gene, Mincle, a C-type lectin receptor, that senses non-homeostatic cell death, thereby inducing pro-inflammatory cytokine and chemokine production. Mincle expression was induced in liver of ALD patients and in mice after ethanol feeding in an IRAKM-dependent pathway. Further, Mincle-deficient mice were protected from ethanol-induced liver injury. Since Mincle is a sensor for cell death and its expression is IRAKM-dependent, we hypothesize that TLR-induced IRAKM-dependent Mincle up-regulation in Kupffer cells provides a critical link between alcohol-induced cell death and onset of inflammatory responses, contributing to the pathogenesis of ALD. To test this hypothesis, we propose the following Aims: Aim 1 Investigate the mechanism for TLR-mediated IRAKM-dependent pathway in ALD: we will investigate (1) The molecular mechanism for the TLR-MyD88-IRAKM-MEKK3-dependent pathway induced by low dose of TLR ligands; (2) The mechanism for the pathogenic role of the TLR-MyD88-IRAKM-MEKK3-dependent pathway in ALD. Aim 2 Investigate the mechanism by which Mincle-mediated signaling contributes to ALD: We will investigate (1) The molecular mechanism for Mincle-mediated inflammasome activation; (2) The cellular mechanism for the pathogenic role of the Mincle-dependent pathway in ALD. These combined molecular/cellular and pre-clinical studies will identify critical elements in the role of the TLR-IRAK-M-Mincle signaling in ALD, leading to improved therapeutics for prevention and treatment of ALD.

描述（由适用提供）：酒精性肝病（ALD）是与酒精有关的发病率和死亡率的主要来源。据估计，有10-15％的酗酒者患有纤维化，肝硬化和肝细胞癌。炎症反应是疾病进展的关键因素。增加感染增加的一项重要途径是由于肠道通透性增加和细菌菌群变化而导致的，导致在库普夫细胞上激活Toll样受体4（TLR4）。但是，乙醇也直接损伤了肝细胞。我们的初步数据表明，受伤的肝细胞信号对于肝巨噬细胞的激活也至关重要。该提案的总体目的是研究TLR依赖性炎症反应如何结合酒精诱导的肝细胞损伤，并协同导致ALD的发病机理。 TLR通过适配器MyD88和IL-1R相关激酶（IRAK）家族的成员（包括Irak1，Irak2，Irak2，Irakm和Irakm和Irak4）传递信号。上游激酶Irak4直接与MyD88相互作用。 MYD88-IRAK4-IRAK1介导TAK1依赖性NFB激活，而MYD88-IRAK4-IRAK2对于转录后控制至关重要。虽然IRAKM与MyD88-IRAK4相互作用以介导MEKK3依赖性的第二波NFB激活，但它与IRAK2相互作用以抑制细胞因子和趋化因子的翻译。这是Irakm对炎症反应产生总体抑制作用。令人惊讶的是，我们发现伊拉克姆缺陷小鼠受到乙醇诱导的肝损伤的保护。阵列分析使我们对一种特定的TLR4诱导的IRAKM依赖性基因Mincle（一种C型凝集素受体）感兴趣，该基因是一种感受非底层细胞死亡的C型凝集素受体，从而诱导促炎性细胞因子和趋化因子的产生。在IRAKM依赖性途径中乙醇进食后，ALD患者和小鼠的肝脏中诱导了Mincle的表达。此外，保护小鼠受到乙醇诱导的肝损伤的保护。由于Mincle是细胞死亡的传感器，其表达依赖于IRAKM，因此我们假设TLR诱导的Kupffer细胞中TLR诱导的Mincle上调提供了与酒精诱导的细胞死亡与炎症反应的发作之间的关键联系，从而有助于ALD的病原体。为了检验这一假设，我们提出了以下目的：目标1研究了ALD中TLR介导的IRAKM依赖途径的机制：我们将研究（1）TLR-MYD88-MYDRAKM-MEKK3依赖性途径的分子机制，由TLR Ligands的低剂量诱导；（2）ALD中TLR-MYD88-MYDMEKM-MEKK3依赖途径的致病作用机制。 AIM 2研究了Mincle介导的信号传导对ALD造成的机制：我们将研究（1）Mincle介导的炎性体激活的分子机制；（2）ALD中Mincle依赖性途径致病作用的细胞机制。这些结合的分子/细胞和临床前研究将确定TLR-IRAK-M-MINCLE信号在ALD中的作用中的关键因素，从而改善了预防和治疗ALD的治疗。