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）：许多动物和人体研究已证明角蛋白中间丝（IF）蛋白在几种急性和慢性肝病中具有重要的保肝功能。由角蛋白8和18（K8/K18）异二聚体组成的肝细胞IF细胞骨架经历由翻译后修饰介导的广泛的生理和疾病相关重组。富含角蛋白的肝细胞马洛里-登克小体（MDB）和影响细胞骨架的其他组织学改变（如肝细胞气球样变）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突出特征。本申请的目的是了解角蛋白类小泛素化的调节、功能意义和肝脏疾病相关性。SUMO化是一种新型的泛素样小分子修饰蛋白的翻译后修饰，在人类疾病的发病机制中具有重要意义。该提议的中心假设是应激诱导的角蛋白类小泛素化参与与其他翻译后修饰的串扰，以在肝损伤期间调节角蛋白性质和功能。三个具体目标将追求：（i）表征应激诱导的K8/K18类小泛素化背后的调控机制;（ii）确定K8/K18类小泛素化的功能意义;（iii）检查代谢性肝病中K8/K18类小泛素化的调控和意义。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学;获得细胞代谢信号传导和代谢性肝病动物模型的专业知识;并具备成为成功的独立研究者所需的技能。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的专家，获得终身教职，并成为一名成功的校外资助的独立研究员，领导消化系统疾病相关研究的强大研究计划。该研究将在一流的机构（密歇根大学）进行，并将涉及消化系统疾病相关研究的领导者的主要指导;代谢信号，糖尿病和胰岛素抵抗的两位专家的共同指导;以及与肝脏病理学，蛋白质组学和翻译后蛋白质调控的三位专家的合作。拟议的研究将提供对代谢和氧化性肝损伤期间角蛋白调节的机制理解，并可能作为治疗常见肝脏疾病（如ALD和NASH）的新方法的基础，这些疾病迫切需要药物干预。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。