Proteotoxicity in the Pathophysiology of Chronic Pancreatitis

摘要 胰腺炎是一种炎症性疾病，具有巨大的健康和经济负担，缺乏既定的 防止复发或进展为慢性病的治疗。我们的长远目标是发展 这些疾病的治疗方法。缺乏有效的治疗方法在一定程度上是由于我们对 关于胰腺炎的病理生理学。目前流行的胰酶依赖模型认为细胞内 胰酶原的激活和导致胰酶失活的保护机制的失效是 发病机制。尽管做了很大的努力，但胰酶在胰腺炎中的作用仍然是推测的和不完全的。 已定义。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，正常蛋白质稳态的破坏和内质网过载通路的激活。结果, 突变蛋白的表达对腺泡细胞是有毒的，并增加了患胰腺炎的风险。有了这个 模型，开发新疗法的方法将与基于 胰酶依赖模型。在这里，我们提出了一种假设，即羧酯脂肪酶(CEL)突变 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 一种炎症反应，增加了细胞对代谢应激损伤的敏感性。CEL突变 发生在含有数量可变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变异体在细胞内以聚集体的形式积累并激活适应性细胞信号 小路。我们提出了以下具体目标：1)确定处理的细胞途径 CEL Vntr变异体的不可溶聚集体；2)鉴定由 CEL VNTR变异体的表达；3)证实了我们在表达CEL VNTR的小鼠模型中的体外结果 胰腺中的变异。通过建议的研究所获得的知识将改善整体 了解胰腺损伤，并为潜在的药物干预提供洞察力 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.