Mechanisms of Trypsin Activation in Pancreatitis

胰腺炎中胰蛋白酶激活的机制

基本信息

批准号：
10587286
负责人：
Andrea Geisz
金额：
$ 36.3万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-09 至 2028-01-31
项目状态：
未结题

项目摘要

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.

抽象的该拨款提案的主要目标为“胰蛋白酶激活机制” 胰腺炎“是为了确定消化蛋白酶胰蛋白酶在体内被激活的过程胰蛋白酶原过早地异位激活为胰蛋白酶。然而，胰腺炎发生的最早事件之一。随着动物实验和人类遗传研究的进展，胰腺内胰蛋白酶的激活仍然存在争议。研究指出了不同的激活途径，因此，胰蛋白酶原可能被组织蛋白酶 B 激活，但当胰蛋白酶激活胰蛋白酶原时，它也可以进行自动激活。这两种与胰腺炎发病相关的胰蛋白酶激活机制尚不清楚。针对这一知识差距，我们提出了三种不同的胰蛋白酶原激活方案：1) 在缺乏胰蛋白酶原的情况下。基因突变引起的胰蛋白酶原自动激活增加，组织蛋白酶 B 可诱导显着 (2)如果基因突变胰蛋白酶原适度增加自激活，实验诱发的胰腺炎的严重程度将 (3) 最后，如果基因发生改变引起强烈的胰蛋白酶原自动激活、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决定。在本拨款提案中，我们将测试每一项。这三种病理情况使用具有胰蛋白酶原突变的独特小鼠模型。拟议项目的成功完成将为发病机制提供新的机制见解胰腺炎的研究，并将促进新的治疗和预防方法的开发。