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: 9111266
• 负责人: Natasha T Snider
• 金额: $ 3.78万
• 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/9111266
• 关键词: Keratin; sumoylation; its; function; during

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）蛋白在几种急性和慢性肝脏疾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）异源二聚体组成，通过翻译后修饰介导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，如肝细胞球囊化，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。本应用程序的目的是了解角蛋白酰化的调节，功能意义和肝脏疾病的相关性。Sumoylation是由小泛素样修饰蛋白（Small Ubiquitin-like Modifier， SUMO）进行的一种新的翻译后修饰，在人类疾病的发病机制中具有重要意义。该建议的中心假设是应激诱导的角蛋白融合化参与了与其他翻译后修饰的串扰，以调节肝损伤过程中角蛋白的特性和功能。将追求三个具体目标：(i)描述应激诱导的K8/K18聚合化背后的调节机制；（ii）确定K8/K18 sumoylation的功能意义；（iii）探讨K8/K18酰化在代谢性肝病中的调节作用及其意义。通过提出的研究和培训计划，候选人将实现的目标包括：学习研究蛋白质功能和调控的新技术；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；并掌握成为一名成功的独立调查员所需的技能。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者，领导一个强大的消化疾病相关研究项目。该研究将在一流机构（密歇根大学）进行，并将由消化疾病相关研究的领导者进行主要指导；2名代谢信号、糖尿病和胰岛素抵抗专家共同指导；并与肝脏病理学、蛋白质组学和翻译后蛋白调控方面的三位专家合作。拟议的研究将提供代谢和氧化性肝损伤过程中角蛋白调控的机制理解，并可能作为治疗常见肝脏疾病的新方法的基础，如ALD和NASH，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。