RIP3-mediated necroptosis and ethanol-induced liver injury

RIP3介导的坏死性凋亡和乙醇诱导的肝损伤

基本信息

批准号：
8734300
负责人：
Sanjoy Roychowdhury
金额：
$ 18.26万
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：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734300
关键词：
Address Alcoholic Liver Diseases Alcoholic liver damage Alcohols Apoptosis Attenuated CYP2E1 gene Carbon Tetrachloride Caspase Cell Death Cells Cessation of life Chronic Cirrhosis Ethanol Exposure to Fatty Liver Fibrosis Heavy Drinking Hepatocyte Image Inflammation Inflammatory Inhibition of Apoptosis Injury Ischemia Life Ligands Liver Mediating Mediator of activation protein Mitochondria Modeling Molecular Molecular Target Mus Necrosis Oxidative Stress Pathology Pathway interactions Patients Permeability Prevention Process Production Protein Kinase RIPK3 gene Reperfusion Therapy Series Signal Pathway Signal Transduction Steatohepatitis TLR4 gene TNFRSF1A gene Testing Therapeutic Therapeutic Intervention Time Tumor Necrosis Factor Ligand Superfamily Member 6 Work alcohol response base cell injury cell type chemokine cytokine feeding human RIPK1 protein inhibitor/antagonist knock-down liver inflammation liver injury liver transplantation mitochondrial dysfunction new therapeutic target novel prevent release of sequestered calcium ion into cytoplasm research study

项目摘要

DESCRIPTION (provided by applicant): Although apoptosis has been associated with the progression of alcohol-induced liver injury, no direct evidence demonstrates that inhibition of apoptosis actually prevents alcoholic liver damage. We found that inhibition of apoptosis did not, in fact, attenuate ethanol-induced hepatocyte injury, expression of pro- inflammatory cytokines/chemokines or oxidative stress in Bid-deficient mice. Recently, a newly described mode of cell death, called necroptosis, has been implicated in caspase-independent cell injury in a variety of cell types. Necroptosis is activated in a fashion similar to apoptosis, but morphologically, the process resembles necrosis. Signaling mechanisms involving receptor-interacting protein kinases (RIP), including RIP1 and RIP3, mediate necroptosis induced by the activation of death ligands, including TNFa or Fas. In preliminary studies, we find, for the first time, that expression of RIP3, a central mediator of necroptosis, is increased in mouse livers following chronic ethanol feeding in parallel to the markers of hepatocyte injury. RIP3 is also induced in mouse liver in other models of hepatic injury including carbon tetrachloride (CCl4)- and ischemia/reperfusion-induced liver damage. Moreover, in pilot experiments we now show that RIP3-deficient mouse are protected from ethanol-induced liver injury and inflammation. Here we hypothesize that hepatocyte injury following chronic ethanol feeding is regulated by RIP3-driven caspase-independent cell death. To test our hypothesis, we will use mice deficient in RIP3 as well as treatment with necrostatin-1, a necroptosis inhibitor, during ethanol feeding. We will also use mice deficient in CYP2E1, TNFR1, and TLR4 to determine upstream activators of the RIP3-signaling pathway in response to ethanol feeding. This study will explore new pathways of cell death in mouse liver following ethanol feeding. The proposed work will help us to determine new molecular targets for better therapeutic management of alcoholic liver disease (ALD).

描述（由申请人提供）：尽管凋亡与酒精引起的肝损伤的进展有关，但没有直接证据表明抑制凋亡实际上会阻止酒精性肝损害。我们发现，抑制凋亡实际上并没有减弱乙醇诱导的肝细胞损伤，促炎性细胞因子/趋化因子/趋化因子或氧化应激的表达。最近，一种新描述的细胞死亡模式称为坏死性，在多种细胞类型中与caspase无关的细胞损伤有关。坏死性以类似于凋亡的方式激活，但从形态上讲，该过程类似于坏死。涉及受体相互作用蛋白激酶（RIP）（包括RIP1和RIP3）的信号传导机制介导了由包括TNFA或FAS在内的死亡配体激活引起的坏死性。在初步研究中，我们首次发现，在慢性乙醇喂养后与肝细胞损伤标记并行进食后，小鼠肝脏中RIP3的表达增加了。在其他肝损伤模型（包括四氯化碳（CCL4））和缺血/再灌注诱导的肝损伤的肝损伤模型中，RIP3也是诱导的。此外，在试验实验中，我们现在表明RIP3缺陷小鼠受到乙醇诱导的肝损伤和炎症的保护。在这里，我们假设慢性乙醇进食后的肝细胞损伤受RIP3驱动的caspase无关细胞死亡调节。为了检验我们的假设，我们将在乙醇喂养过程中使用缺乏RIP3的小鼠以及用坏死蛋白1（坏死抑制剂）治疗的小鼠。我们还将使用缺乏CYP2E1，TNFR1和TLR4的小鼠来确定RIP3-信号途径的上游激活剂，以响应乙醇摄食。这项研究将探索乙醇进食后小鼠肝脏中细胞死亡的新途径。拟议的工作将帮助我们确定新的分子靶标，以更好地治疗酒精性肝病（ALD）。