Mechanisms of Trypsin Activation in Pancreatitis

摘要 这项拨款提案的主要目标是“胰酶激活的机制” 胰腺炎“是确定消化酶胰酶在体内被激活的过程。 胰腺并引发胰腺炎。胰酶原对胰酶的过早、异位激活是 胰腺炎发展过程中最早的事件之一。然而，这一机制 由于动物实验和人类基因，胰腺内胰蛋白酶的激活一直存在争议。 研究指出了不同的激活途径。因此，组织蛋白酶B可以激活胰蛋白酶原，但是 当胰酶激活胰酶原时，它也可以自我激活。他们各自的贡献 胰酶激活与胰腺炎发病相关的这两种机制尚不清楚。致信地址 根据这一认识差距，我们提出了三种不同的胰酶原激活方案。1)在以下情况下 基因突变引起的胰蛋白酶原自激活增加，组织蛋白酶B可诱导显著 胰腺内胰酶激活，不影响胰腺炎严重程度。(2)如果基因突变发生在 胰蛋白酶原适度增加自身激活，实验性胰腺炎的严重程度将 依赖于组织蛋白酶B介导的胰蛋白酶原激活的程度。(3)最后，如果基因改变 导致强大的胰酶原自激活，自发性胰腺炎的发病年龄和严重程度是 由组织蛋白酶B介导的胰蛋白酶原激活来确定。在这项拨款提案中，我们将测试每一项 这三种病理情况采用独特的小鼠胰酶原突变模型。 拟议项目的成功完成将为发病机制提供新的机械学见解。 这将有助于开发新的治疗和预防方法。

ABSTRACT The principal objective of this grant proposal entitled “Mechanisms of trypsin activation in pancreatitis“ is to identify the process by which the digestive protease trypsin becomes activated inside the pancreas and initiates pancreatitis. The premature, ectopic activation of trypsinogen to trypsin is one of the earliest events in the development of pancreatitis. However, the mechanism of intrapancreatic trypsin activation has remained contentious as animal experiments and human genetic studies pointed to different activation pathways. Thus, trypsinogen may be activated by cathepsin B but it can also undergo autoactivation, when trypsin activates trypsinogen. The respective contribution of these two mechanisms to trypsin activation associated with pancreatitis onset is unknown. To address this knowledge gap, we propose three distinct scenarios of trypsinogen activation. 1) In the absence of increased trypsinogen autoactivation caused by genetic mutations, cathepsin B can induce significant intrapancreatic trypsin activation, without affecting pancreatitis severity. (2) If genetic mutations in trypsinogen moderately increase autoactivation, severity of experimentally-induced pancreatitis will depend on the degree of cathepsin B-mediated trypsinogen activation. (3) Finally, if a genetic change that causes robust trypsinogen autoactivation, age of onset and severity of spontaneous pancreatitis is determined by cathepsin B-mediated trypsinogen activation. In this grant proposal, we will test each of these three pathological circumstances using unique mouse models with trypsinogen mutations. Successful completion of the proposed project will offer fresh mechanistic insight into the pathogenesis of pancreatitis and will facilitate the development of novel therapeutic and preventive approaches.