Liver Inflammation and Injury: Molecular Mechanisms

肝脏炎症和损伤：分子机制

基本信息

批准号：
8044920
负责人：
MARIO CHOJKIER
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-10-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044920
关键词：
Accounting Acute Acute Liver Failure Alcoholic Hepatitis Alcoholism Apoptosis Apoptotic Area Award Biliary Atresia Biological Sciences CCAAT-Enhancer-Binding Protein-beta CCAAT-Enhancer-Binding Proteins California Cell Cycle Progression Cell-Free System Cells Cellular biology Chronic Cicatrix Cirrhosis Clinical Research Cloning Coculture Techniques Collagen Gene Data Deposition Development Diabetes Mellitus Dominant-Negative Mutation Extracellular Matrix Proteins Fatty Liver Future Gatekeeping Gene Expression Genetic Transcription Graft Rejection Grant Hepatic Stellate Cell Hepatitis Hepatitis B Hepatitis C Immune Immunologics Inflammation Inflammatory Inflammatory Response Injury Kidney Knowledge Kupffer Cells Lead Legal patent Liver Liver Cirrhosis Liver Failure Liver Fibrosis Liver diseases Lung Macrophage Activation Malignant neoplasm of liver Medical Metabolic Diseases Modeling Molecular Mus Obesity Obstructive Liver Cirrhosis Outcome Study Outcomes Research Oxidative Stress Paper Patients Peptides Pharmaceutical Preparations Phase Phenotype Phosphorylation Play Population Prevention Prevention strategy Primary carcinoma of the liver cells Proliferating Publications Reperfusion Injury Reporting Research Personnel Ribosomal Protein S6 Kinase Role Signal Transduction Site Therapeutic Tissues Transactivation Transgenes Transgenic Mice Transgenic Organisms United States Department of Veterans Affairs United States National Institutes of Health Universities Veterans Viral Work Wound Healing base chronic liver disease effective therapy extracellular fibrogenesis hepatotoxin human disease immunoregulation in vivo inhibitor/antagonist insight kinase inhibitor liver transplantation macrophage mimetics mortality mouse model mutant nonalcoholic steatohepatitis novel patient population peptidomimetics prevent primary sclerosing cholangitis programs repaired research and development response ribosomal protein S6 kinase 2 small molecule stellate cell

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT Ours was the original report of the cloning of the CCAAT/Enhancer Binding Protein (C/EBP)b . We have established that site-specific phosphorylations of C/EBPb are critical modulators of gene expression, cell- cycle progression, apoptotic programs, immune modulation and tissue inflammation and repair. C/EBPb-phosphorylation mutant models of human diseases were extensively utilized by us to make these discoveries. Unexpectectly, we have recently determined that phosphorylation of C/EBPb-Thr217 on its transactivation domain by ribosomal S6-kinase (RSK)-2 plays a major role in inducing liver macrophage M1 ('classical', 'pro-inflammatory') activity. This is the first specific phosphorylation known to modulate the macrophage M1 to M2 switch. Identification and characterization of the M1/M2 paradigm may provide new insights into liver macrophage and stellate cell biology as well as potential therapeutic strategies for the prevention and treatment of liver injury. It provides an opportunity to control liver inflammation and injury in patients with acute and chronic liver diseases as well as potential therapeutic strategies for the prevention and treatment of liver inflammation and injury. This novel modulation of liver macrophage M1 pro-inflammatory activity is essential in understanding liver inflammation and injury and its critical role in the activation of stellate cells. SPECIFIC OBJECTIVES This proposal will study the mechanisms by which phosphorylation of C/EBPb-Thr217 modulates the 'inflammatory' M1 macrophage response, thereby, inducing liver inflammation and increasing liver injury. Specific Aim 1. The phosphorylation state of C/EBPb-Thr217 modulates the macrophage M1/M2 phenotype Specific Aim 2. The effects of M1 and M2 liver macrophages on stellate cells activation. Specific Aim 3. The effects of RSK-inhibitory peptides on the macrophage M1/M2 phenotype. Specific Aim 4. Optimization of RSK-inhibitory peptides for the prevention and treatment of liver inflammation and injury. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE In acute and chronic liver diseases, through inflammation and injury induce damage to the liver, resulting in liver failure. Excessive liver damage accounts for the significant complications and mortality among the VA population with acute and chronic liver diseases. The medical and financial burden of liver diseases to the Veteran's Administration is substantial, as it is associated with Hepatitis B and C, rejection of a transplanted liver, auto-immune hepatitis, fatty liver of obesity and diabetes and alcoholism. Additional knowledge gained by this work will add to the understanding of liver inflammation and injury may lead to better treatments. Development of effective treatments for liver inflammation and injury may also facilitate future treatments for lung and kidney inflammation and injury.

描述（由申请人提供）：摘要我们的是CCAAT/增强子结合蛋白（C/EBP）b的克隆的原始报告。我们已经确定C/EBPB的位点特异性磷酸化是基因表达，细胞周期进程，凋亡程序，免疫调节以及组织炎症和修复的关键调节剂。我们广泛利用了人类疾病的C/EBPB磷酸化突变模型来做出这些发现。不可思议地，我们最近确定，通过核糖体S6-激酶（RSK）-2对C/EBPB-THR217的磷酸化在其反式激活结构域上的磷酸化在诱导肝巨噬细胞M1（'classical'，'''in Fromamammatoration）中起主要作用。这是已知将巨噬细胞M1转换为M2开关的第一个特异性磷酸化。 M1/M2范式的鉴定和表征可以为肝巨噬细胞和星状细胞生物学以及预防和治疗肝损伤的潜在治疗策略提供新的见解。它提供了控制急性和慢性肝病患者肝炎和损伤的机会，以及预防和治疗肝脏炎症和损伤的潜在治疗策略。肝巨噬细胞M1促炎活性的这种新型调节对于理解肝脏炎症和损伤及其在星状细胞激活中的关键作用至关重要。具体目标该提案将研究C/EBPB-THR217磷酸化的机制，可调节“炎症” M1巨噬细胞反应，从而诱导肝脏炎症和增加的肝损伤。具体目标1。c/eBPB-thr217的磷酸化状态调节巨噬细胞M1/M2表型特异性目标2。M1和M2肝巨噬细胞对星状细胞激活的影响。具体目标3。RSK抑制性肽对巨噬细胞M1/M2表型的影响。具体目标4。优化RSK抑制性肽用于预防和治疗肝脏炎症和损伤。公共卫生相关性：急性和慢性肝病的项目叙述是通过炎症和损伤引起肝脏损害的，导致肝衰竭。肝脏损害过多造成了急性和慢性肝病的VA人群的显着并发症和死亡率。退伍军人管理的肝病的医疗和财务负担很大，因为它与乙型肝炎和C有关，拒绝移植的肝脏，自身免疫性肝炎，肥胖症和糖尿病和酒精中毒的脂肪肝。这项工作获得的其他知识将增加对肝脏炎症和损伤的理解，这可能会导致更好的治疗方法。开发有效治疗肝脏炎症和损伤的治疗方法也可能促进未来治疗肺部和肾脏炎症和损伤的治疗方法。