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: 8917199
• 负责人: Natasha T Snider
• 金额: $ 15.16万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/8917199
• 关键词: Acetylation; Acute; Address; Affect; Alcohol consumption; Alcoholic Liver Diseases; Animal Model; Animals; Antioxidants; Apoptosis; Area; Binding; Bioenergetics; Biological; Cells; Collaborations; Cytokeratin filaments; Cytoskeleton; Data; Diabetes Mellitus; Digestive System Disorders; Disease; Environment; Enzymes; Epithelium; Exhibits; Faculty; Family; Funding; Genes; Goals; Hepatocyte; Human; Injury; Institution; Insulin; Insulin Resistance; Intermediate Filament Proteins; Intermediate Filaments; Intervention; Investigation; K-18 conjugate; Keratin; Learning; Ligase; Link; Liver; Liver diseases; Lysine; Mediating; Mentorship; Metabolic; Metabolic stress; Michigan; Modeling; Molecular; Mus; Mutation; Nuclear Translocation; Obesity; Organ; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Phosphorylation; Physiological; Pioglitazone; Polymers; Positioning Attribute; Post-Translational Protein Processing; Process; Property; Protein Family; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Training; Resistance; Role; Signal Pathway; Signal Transduction; Sirtuins; Solid; Solubility; Staging; Stress; Susceptibility Gene; Techniques; Testing; Therapeutic; Tissue Polypeptide Specific Antigen; Transgenic Mice; Ubiquitin; Universities; base; biological adaptation to stress; career; chronic liver disease; common treatment; genetic approach; human disease; injured; insight; insulin sensitizing drugs; liver injury; member; mutant; nonalcoholic steatohepatitis; novel; novel strategies; prevent; programs; protein function; response; response to injury; skills

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）：许多动物和人类研究表明，在几种急性和慢性肝疾病中，角蛋白中间丝（IF）蛋白具有重要的肝保护功能。由角蛋白8和18和18（K8/K18）异二聚体组成的肝细胞IF细胞骨架进行了广泛的生理和疾病相关的重组，这些重组是由翻译后修饰介导的。富含角质的肝细胞mallory-denk身体（MDB）以及其他影响细胞骨架的组织学改变，例如肝细胞气球，是酒精性肝病（ALD）的突出特征，非酒精性脂肪性脂肪性肝炎（NASH）（NASH）（NASH），以及其他受氧化损伤和含量为敏感性的疾病。该应用的目的是了解角蛋白Sumoylation的调节，功能意义和肝病相关性。 Sumoylation是一种新型的泛素样修饰剂（SUMO）蛋白的新型翻译后修饰，对人类疾病发病机理具有重要意义。该提议的中心假设是应激诱导的角蛋白sumoylation参与与其他翻译后修饰的交叉对话，以调节肝损伤期间角蛋白特性和功能。将追求三个具体目标：（i）表征压力引起的K8/K18 Sumoylation背后的调节机制； （ii）确定K8/K18 sumoylation的功能意义； （iii）检查代谢性肝病中K8/K18 Sumoylation的调节和重要性。候选人将通过拟议的研究和培训计划实现的目标包括：学习研究蛋白质功能和调节的新技术；善于分析人类和动物病理；在代谢肝病的细胞代谢信号传导和动物模型方面获得专业知识；并以成为成功的独立调查员所需的技能为基础。候选人的长期职业目标是成为中间细丝蛋白及其在人类疾病中的角色，获得终身教师职位，并成为一项成功的外部资助的独立研究者，领导着消化疾病相关研究的强大研究计划。这项研究将在一家总理机构（密歇根大学）进行，并将涉及消化疾病相关研究领导者的主要指导；两位代谢信号传导，糖尿病和胰岛素抵抗的专家共同训练；以及与三位肝病学，蛋白质组学和翻译后蛋白质调节专家的合作。拟议的研究将提供对代谢和氧化肝损伤过程中角蛋白调节的机械理解，并可以作为治疗常见肝疾病的新方法的基础，例如ALD和NASH，在这些方法中需要进行严格的药理干预措施。重要的是，这些研究将为候选人在其独立的研究职业阶段将为候选人提供新的调查机会。