Organelle Disorders in Pancreatitis

总体研究策略：摘要/摘要 胰腺炎是一种潜在的致命性疾病，具有显著的发病率和死亡率，其发病机制 仍然鲜为人知。目前还缺乏预防胰腺炎或减少损伤的具体治疗方法。建议的计划 重点介绍了胰腺腺泡细胞中的关键器官细胞的紊乱，这是引发 以及引发胰腺炎。腺泡细胞的生理功能是合成、运输、储存和 分泌消化酶。这些功能依赖于内质网(ER)的作用，即内质网、内质网和内质网的作用。 溶酶体系统和自噬来协调蛋白质的合成、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： 调节蛋白质加工、运输和降解的腺泡细胞细胞器机制 启动和促进胰腺炎的细胞病理学。我们提出了四个使用 在急性胰腺炎的背景下研究以下内容的多学科方法：KEY 蛋白转运调节因子Rab GTP酶在内体和溶酶体/自噬功能障碍中的作用 胰腺炎(项目1)；调节蛋白D52、Rab5和AP3在抑制分泌和 细胞内酶原激活(项目2)；多功能支架蛋白p62/SQSTM1和 自噬受损在胰腺炎发病机制中的作用(项目3)：内质网应激反应的作用，以及 特别是内质网应激调节因子sXBP1在内体功能缺陷、自噬和分泌中的作用 抑制(项目4)。这些项目使用了三个支持核心，它们将执行标准化的动物模型 野生型和转基因小鼠的胰腺炎，产生新的小鼠系，提供组织病理学 人胰腺组织的评价，人腺泡细胞的分离，小鼠和小鼠的病毒转导 人腺泡细胞，以及基于Web的资源库和数据共享系统。因此，该计划将 阐明关键腺泡细胞器紊乱所致胰腺炎的新致病机制； 确定新的分子靶点，促进疾病治疗新方法的发展 治疗；整合和催化具有不同专业知识领域的调查人员的工作，以确定 胰腺炎的发病机制。

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.