Keratin sumoylation and its function during hepatocyte stress and liver disease

角蛋白苏酰化及其在肝细胞应激和肝脏疾病中的功能

• 批准号: 8333967
• 负责人: Natasha T Snider
• 金额: $ 10.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333967
• 关键词: 2,4-thiazolidinedione; Abbreviations; Acetylation; Acute; Address; Affect; Alcohol consumption; Alcoholic Liver Diseases; Animal Model; Animals; Antioxidants; Apoptosis; Area; Binding; Bioenergetics; Biological; Cells; Collaborations; Cytokeratin filaments; Cytoskeleton; Data; Deacetylase; Diabetes Mellitus; Digestive System Disorders; Dimethyl Sulfoxide; Disease; Environment; Enzymes; Epithelium; Exhibits; Faculty; Family; Funding; Genes; Genetic; Glyceraldehyde-3-Phosphate Dehydrogenases; Goals; Hepatocyte; Human; Hydrogen Peroxide; Injury; Institution; Insulin; Insulin Resistance; Intermediate Filament Proteins; Intermediate Filaments; Intervention; Investigation; K-18 conjugate; Keratin; Learning; Ligase; Link; Liver; Liver diseases; Lysine; MAP Kinase Gene; Mallory Body; Mediating; Mentorship; Metabolic; Metabolic stress; Michigan; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Mutation; Nuclear Translocation; Obesity; Organ; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Peroxonitrite; Phosphorylation; Physiological; Pioglitazone; Polymers; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Process; Property; Protein Family; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Training; Resistance; Role; Signal Pathway; Signal Transduction; Sirtuins; Small Ubiquitin-Related Modifier Proteins; Solid; Solubility; Staging; Stress; Techniques; Testing; Therapeutic; Thiazolidinediones; Tissue Polypeptide Specific Antigen; Transgenic Mice; Ubiquitin; Universities; Variant; base; biological adaptation to stress; career; chronic liver disease; common treatment; human disease; inhibitor/antagonist; injured; insight; insulin sensitizing drugs; member; mutant; nonalcoholic steatohepatitis; novel; novel strategies; prevent; programs; protein function; protein inhibitors of activated STAT; response; response to injury; skills; sulfoenolpyruvate

DESCRIPTION (provided by applicant): Numerous animal and human studies have demonstrated an important hepatoprotective function of keratin intermediate filament (IF) proteins in several acute and chronic liver diseases. The hepatocyte IF cytoskeleton, which consists of keratin 8 and 18 (K8/K18) heterodimers, undergoes extensive physiological and disease- related reorganization that is mediated by post-translational modifications. Keratin-rich hepatocyte Mallory- Denk bodies (MDBs), and other histological alterations affecting the cytoskeleton, such as hepatocyte ballooning, are prominent features of alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), and other diseases characterized by oxidative injury and metabolic abnormalities. The objective of this application is to understand the regulation, functional significance, and liver disease relevance of keratin sumoylation. Sumoylation is a novel post-translational modification by Small Ubiquitin-like Modifier (SUMO) proteins with important implications to human disease pathogenesis. The central hypothesis of this proposal is that stress- induced keratin sumoylation participates in cross-talk with other post-translational modifications to regulate keratin properties and function during liver injury. Three specific aims will be pursued: (i) Characterize the regulatory mechanisms behind stress-induced K8/K18 sumoylation; (ii) Determine the functional significance of K8/K18 sumoylation; and (iii) Examine the regulation and significance of K8/K18 sumoylation in metabolic liver disease. The goals that the candidate will achieve through the proposed research and training plan include: learning novel techniques to study protein function and regulation; becoming adept at analysis of human and animal pathology; gaining expertise in cellular metabolic signaling and animal models of metabolic liver disease; and becoming grounded with the skills needed to become a successful independent investigator. The candidate's long-term career goals are to become an expert on intermediate filament proteins and their roles in human diseases, obtain a tenure-track faculty position and become a successful extramurally-funded independent investigator leading a strong research program in digestive disease related research. The research will be carried out at a premier institution (University of Michigan) and will involve primary mentorship from a leader in digestive disease related research; co-mentorship by two experts of metabolic signaling, diabetes, and insulin resistance; and collaborations with three experts of liver pathology, proteomics and post- translational protein regulation. The proposed research will provide mechanistic understanding of keratin regulation during metabolic and oxidative liver injury and may serve as the basis for novel approaches to treat common liver diseases, like ALD and NASH, where pharmacologic interventions are critically needed. Importantly, these studies will create new opportunities for investigation that the candidate will pursue during her independent research career stage.

描述(由申请人提供)：大量的动物和人体研究表明，角蛋白中间丝(IF)蛋白在几种急慢性肝病中具有重要的肝脏保护功能。肝细胞IF细胞骨架由角蛋白8和18(K8/K18)异二聚体组成，通过翻译后修饰进行广泛的生理和疾病相关的重组。富含角蛋白的肝细胞Mallory-Denk小体(MDB)和其他影响细胞骨架的组织学改变，如肝细胞膨胀，是酒精性肝病(ALD)、非酒精性脂肪性肝炎(NASH)和其他以氧化损伤和代谢异常为特征的疾病的显著特征。这项应用的目的是了解角蛋白和甲基化的调节、功能意义和与肝脏疾病的相关性。SUMO是一种新的泛素样修饰物(SUMO)蛋白的翻译后修饰，在人类疾病发病机制中具有重要意义。这一建议的中心假设是，应激诱导的角蛋白和甲基化参与了与其他翻译后修饰的串扰，以调节肝脏损伤期间的角蛋白特性和功能。我们将追求三个特定的目标：(I)确定应激诱导的K8/K18相加作用背后的调控机制；(Ii)确定K8/K18相加作用的功能意义；(Iii)研究K8/K18相加作用在代谢性肝病中的调节和意义。通过拟议的研究和培训计划，候选人将实现的目标包括：学习研究蛋白质功能和调节的新技术；熟练分析人类和动物病理；获得细胞代谢信号和代谢性肝病动物模型方面的专业知识；以及掌握成为一名成功的独立研究人员所需的技能。候选人的长期职业目标是成为中间丝蛋白及其在人类疾病中的作用方面的专家，获得终身教职，并成为一名成功的外部资助的独立研究员，领导与消化疾病相关研究的强大研究计划。这项研究将在一流机构(密歇根大学)进行，将包括一位消化系统疾病相关研究领先者的初级指导；两位代谢信号、糖尿病和胰岛素抵抗专家的共同指导；以及三位肝脏病理学、蛋白质组学和翻译后蛋白质调节的专家的合作。这项拟议的研究将提供对代谢和氧化性肝损伤过程中角蛋白调节的机制理解，并可能成为治疗ALD和NASH等常见肝病的新方法的基础，在这些疾病中，迫切需要药物干预。重要的是，这些研究将创造新的调查机会，候选人将在她的独立研究生涯阶段追求这些机会。