Liver Inflammation and Injury: Molecular Mechanisms

肝脏炎症和损伤：分子机制

• 批准号: 8597338
• 负责人: MARIO CHOJKIER
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 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/8597338
• 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 Fibrogenesis; 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; base; chronic liver disease; effective therapy; extracellular; hepatotoxin; human disease; immunoregulation; in vivo; inhibitor/antagonist; insight; kinase inhibitor; liver inflammation; liver injury; liver transplantation; macrophage; mimetics; mortality; mouse model; mutant; nonalcoholic steatohepatitis; novel; patient population; peptidomimetics; prevent; primary sclerosing cholangitis; programs; public health relevance; repaired; research and development; response; ribosomal protein S6 kinase 2; small molecule; stellate cell; tissue repair

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)： 摘要我们首次报道了CCAAT/增强子结合蛋白(C/EBP)b的克隆。我们已经证实，C/EBPB的位点特异性磷酸化是基因表达、细胞周期进展、凋亡程序、免疫调节以及组织炎症和修复的关键调节器。人类疾病的C/EBPB-磷酸化突变模型被我们广泛地应用于这些发现。出人意料的是，我们最近确定核糖体S6-激酶(RSK)-2在其反式激活区域C/EBPB-Thr217的磷酸化在诱导肝巨噬细胞M1(经典的、促炎的)活性中起主要作用。这是已知的第一个调节巨噬细胞M1到M2开关的特异性磷酸化。M1/M2模式的识别和表征可能为了解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。它为控制急慢性肝病患者的肝脏炎症和损伤提供了机会，并为预防和治疗肝脏炎症和损伤提供了潜在的治疗策略。这种对肝脏巨噬细胞M1促炎活性的新调节对于了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。具体目的本研究将研究C/EBPB-Thr217磷酸化调控炎症性M1巨噬细胞反应的机制，从而诱导肝脏炎症和增加肝脏损伤。特异性目的1.C/EBPB-Thr217的磷酸化状态调节巨噬细胞M1/M2表型特异性目的2.肝巨噬细胞M1和M2对星状细胞激活的影响。特定目的3.RSK抑制肽对巨噬细胞M1/M2表型的影响。具体目的4.用于防治肝脏炎症和损伤的RSK抑制肽的优化。 公共卫生相关性： 项目简介在急性和慢性肝病中，通过炎症和损伤导致肝脏损伤，导致肝功能衰竭。在患有急慢性肝病的退伍军人中，过度的肝损伤是导致严重并发症和死亡的主要原因。肝脏疾病给退伍军人管理局带来了沉重的医疗和财政负担，因为它与乙肝和丙型肝炎、移植肝脏排斥反应、自身免疫性肝炎、肥胖症和糖尿病脂肪肝以及酗酒有关。通过这项工作获得的更多知识将增加对肝脏炎症和损伤的理解，可能会导致更好的治疗。针对肝脏炎症和损伤的有效治疗方法的发展也可能促进未来对肺和肾脏炎症和损伤的治疗。