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

基本信息

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
项目类别：
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

项目摘要

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）：大量动物和人类研究已经证明角蛋白中间丝（IF）蛋白在多种急性和慢性肝病中具有重要的保肝功能。肝细胞 IF 细胞骨架由角蛋白 8 和 18 (K8/K18) 异二聚体组成，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 Mallory-Denk 小体 (MDB) 和其他影响细胞骨架的组织学改变，例如肝细胞气球样变，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炎症为特征的疾病的显着特征。代谢异常。本申请的目的是了解角蛋白苏酰化的调节、功能意义和肝脏疾病相关性。 Sumoylation 是小泛素样修饰 (SUMO) 蛋白的一种新型翻译后修饰，对人类疾病发病机制具有重要意义。该提议的中心假设是，应激诱导的角蛋白苏酰化参与与其他翻译后修饰的串扰，以调节肝损伤期间的角蛋白特性和功能。我们将追求三个具体目标： (i) 表征应激诱导的 K8/K18 sumoylation 背后的调控机制； (ii) 确定 K8/K18 sumoylation 的功能意义； (iii) 检查 K8/K18 苏酰化在代谢性肝病中的调节和意义。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；擅长分析人类和动物病理学；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；并具备成为一名成功的独立调查员所需的技能。该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，获得终身教授职位，并成为一名成功的外部资助的独立研究者，领导消化疾病相关研究的强大研究项目。该研究将在顶级机构（密歇根大学）进行，并将得到消化疾病相关研究领导者的主要指导；由代谢信号、糖尿病和胰岛素抵抗领域的两位专家共同指导；并与肝脏病理学、蛋白质组学和翻译后蛋白质调控领域的三位专家合作。拟议的研究将提供对代谢性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，这些研究将为候选人在其独立研究生涯阶段所追求的调查创造新的机会。