Organelle Disorders in Pancreatitis

胰腺炎的细胞器疾病

• 批准号: 8743013
• 负责人: ANNA S. GUKOVSKAYA
• 金额: $ 167.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743013
• 关键词: Acinar Cell; Animal Model; Animals; Area; Automobile Driving; Autophagocytosis; Binding Proteins; Biostatistics Core; Cell Death; Cell model; Collaborations; Databases; Defect; Development; Disease; Disorder by Site; Endoplasmic Reticulum; Enzyme Precursors; Enzymes; Evaluation; Experimental Models; Functional disorder; Funding; Generations; Genetic Models; Goals; Golgi Apparatus; Heat shock proteins; Human; Inflammation; Injury; Lead; Maintenance; Mediating; Minor; Molecular Target; Morbidity - disease rate; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Online Systems; Organelles; Pancreas; Pancreatitis; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiological; Process; Protein Biosynthesis; Proteins; Publishing; Recording of previous events; Research; Research Personnel; Research Project Grants; Resources; Role; Scaffolding Protein; Scientist; Secure; Signal Transduction; Sum; System; TPD52 gene; Tissues; Trypsinogen; United States National Institutes of Health; Viral; Work; abstracting; acute pancreatitis; animal tissue; arm; base; biological adaptation to stress; cellular pathology; data sharing; effective therapy; endoplasmic reticulum stress; experience; genetic regulatory protein; human tissue; in vivo; interdisciplinary approach; mortality; mouse model; novel; novel therapeutic intervention; prenylation; prevent; programs; protein aggregate; protein degradation; protein transport; rab GTP-Binding Proteins; response; stress protein; therapeutic target; trafficking; treatment strategy; vector

Overall Research Strategy: Summary/Abstract Pancreatitis is a potentially fatal disease with significant morbidity and mortality the pathogenesis of which remains obscure. Specific therapies to prevent pancreatitis or reduce injury are lacking. The proposed Program focuses on disorders of key orgenells in the pancreatic acinar cell as a central pathogenic mechanism initiating and driving pancreatitis. The physiologic function of the acinar cell is to synthesize, transport, store, and secrete digestive enzymes. These functions rely on the actions of endoplasmic reticulum (ER), the endo- lysosomal system and autophagy to coordinate protein synthesis, processing, trafficking and degradation. Based on our published and preliminary studies, we propose the following novel hypothesis: dysfunction of acinar cell organellar machinery that mediates protein processing, trafficking, and degradation initiates and promotes the cellular pathology of pancreatitis. We propose four Projects that use multidisciplinary approaches to study the following in the context of acute pancreatitis: The role of key regulators of protein trafficking, Rab GTPases, in endosomal and lysosomal/autophagic dysfunction in pancreatitis (Project 1); The role of regulatory proteins D52, Rab5 and AP3 in inhibition of secretion and intracellular zymogen activation (Project 2); The roles of the multifunctional scaffold protein p62/SQSTM1 and impaired autophagy in the pathogenesis of pancreatitis (Project 3); The role of ER stress responses, and particularly the ER stress regulator sXBP1, in defective endosomal function, autophagy, and secretion inhibition (Project 4). The Projects use three supporting Cores which will perform standardized animal models of pancreatitis on wild-type and genetically modified mice, generate new mouse lines, provide histopathologic evaluation of human pancreatic tissue, isolation of human acinar cells, viral transduction of both mouse and human acinar cells, and Web-based resource repository and data sharing system. Thus, the Program will elucidate novel pathogenic mechanisms of pancreatitis resulting from disorders of key acinar cell organelles; identify new molecular targets and promote the development of new therapeutic approaches for disease treatment; integrate and catalyze the work of investigators with various areas of expertise to define the mechanism of pancreatitis.

总体研究策略：摘要/摘要 胰腺炎是一种具有显著发病率和死亡率的潜在致命性疾病，其发病机制 仍然模糊。缺乏预防胰腺炎或减少损伤的特定疗法。拟议程序 重点是胰腺腺泡细胞中的关键器官细胞的疾病， 和急性胰腺炎腺泡细胞的生理功能是合成、运输、储存和分泌腺泡蛋白。 分泌消化酶。这些功能依赖于内质网（ER）的作用， 溶酶体系统和自噬以协调蛋白质合成、加工、运输和降解。 基于我们已发表的和初步的研究，我们提出了以下新的假设： 介导蛋白质加工、运输和降解的腺泡细胞细胞器机制 启动并促进胰腺炎的细胞病理学。我们提出了四个项目， 多学科方法研究急性胰腺炎的背景下：关键的作用 蛋白质运输的调节剂，Rab GTP酶，在核内体和溶酶体/自噬功能障碍中， 胰腺炎（项目1）;调节蛋白D52、Rab 5和AP 3在抑制分泌和 细胞内酶原激活（项目2）;多功能支架蛋白p62/SQSTM 1和 胰腺炎发病机制中的自噬受损（项目3）;内质网应激反应的作用， 特别是ER应激调节因子sXBP 1，在有缺陷的内体功能、自噬和分泌中 抑制（项目4）。该项目使用三个支持核心，将执行标准化的动物模型 胰腺炎的野生型和转基因小鼠，产生新的小鼠品系，提供组织病理学 人胰腺组织的评价，人腺泡细胞的分离，小鼠和 人类腺泡细胞，以及基于网络的资源库和数据共享系统。因此，该方案将 阐明关键腺泡细胞器紊乱导致胰腺炎的新致病机制; 确定新的分子靶点，促进疾病新治疗方法的开发 治疗;整合和促进具有不同专业领域的研究人员的工作，以确定 胰腺炎的发病机制