Proteotoxicity in the Pathophysiology of Chronic Pancreatitis

摘要 胰腺炎是一种炎症性疾病，具有显著的健康和经济负担， 预防复发或进展为慢性疾病的治疗。我们的长期目标是发展 治疗这些疾病。缺乏有效的治疗方法，部分原因是我们对 胰腺炎的病理生理学流行的胰蛋白酶依赖模型认为，细胞内 胰蛋白酶原激活和负责胰蛋白酶失活的保护机制的失效是 发病机制尽管做了大量的努力，胰蛋白酶在胰腺炎中的作用仍然是推测性的和不完全的 定义了最近的研究表明，外分泌突变患者的另一种疾病机制 蛋白质，破坏正常的蛋白质稳态和激活ER超载途径。因此，在本发明中， 突变蛋白的表达对腺泡细胞是有毒的，并增加胰腺炎的风险。与此 模型，开发新疗法的方法将与基于 胰蛋白酶依赖模型在这里，我们解决的假设，羧基酯脂肪酶（CEL）突变体 与慢性胰腺炎相关的激活适应性细胞信号通路和细胞死亡通路，启动 炎症反应和增加细胞对代谢应激损伤的敏感性。CEL突变 发生在含有可变数目的富含脯氨酸的串联重复序列（VNTR）的区域。我们的初步数据 显示DEL变体在细胞内作为聚集体积累并激活适应性细胞信号传导 途径。我们提出了以下具体目标：1）确定细胞途径的处置 CEL VNTR变体的不溶性聚集体; 2）鉴定由以下激活的适应性细胞信号传导途径： 3）证实我们在表达CEL VNTR的小鼠模型中的离体结果 胰腺的变异通过拟议的研究获得的知识将改善整体 了解胰腺损伤，并提供针对胰腺损伤的潜在药理学干预的见解。 新的治疗靶点蛋白质稳态

Abstract Pancreatitis is an inflammatory disease with significant health and economic burdens that lacks an established therapy to prevent recurrent episodes or progression to chronic disease. Our long-term goal is to develop therapies for these diseases. The absence of effective therapies stems in part from our limited understanding about the pathophysiology of pancreatitis. The prevailing trypsin-dependent model holds that intracellular trypsinogen activation and failure of protective mechanisms responsible for trypsin inactivation are central to pathogenesis. Despite great effort the role of trypsin in pancreatitis remains speculative and incompletely defined. Recent studies suggest another mechanism for disease in patients with mutations in exocrine proteins, disruption of normal protein homeostasis and activation of ER overload pathways. As a result, expression of the mutant proteins is toxic to acinar cells and increases the risk for pancreatitis. With this model, the approach to developing new therapeutics would differ significantly from approaches based on the trypsin-dependent model. Herein, we address the hypothesis that carboxyl ester lipase (CEL) mutants associated with chronic pancreatitis activate adaptive cell signaling pathways and cell death pathways, initiate an inflammatory response and increase susceptibility of cells to injury by metabolic stress. The CEL mutations occur in the region containing a variable number of proline-rich tandem repeats (VNTR). Our preliminary data show that the DEL variants accumulate within the cells as aggregates and activate adaptive cell signaling pathways. We propose the following Specific Aims: 1) Determine the cellular pathways for the disposal of insoluble aggregates of CEL VNTR variants; 2) Identify the adaptive cell signaling pathways activated by expression of CEL VNTR variants; 3) Confirm our ex vivo results in mouse models that express CEL VNTR variants in the pancreas. The knowledge gained by the proposed studies will improve the overall understanding of pancreatic injury and provide insight into potential pharmacological interventions directed at a new therapeutic target, protein homeostasis.