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.

抽象的该赠款提案的主要目标，标题为“胰蛋白酶激活的机制胰腺炎”是为了确定消化蛋白胰蛋白酶在内部激活的过程胰腺并启动胰腺炎。胰蛋白酶原对胰蛋白酶的过早激活是胰腺炎发育中最早的事件之一。但是，机制作为动物实验和人类遗传研究指出不同的激活途径。那就是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，它也可以自动活化。相对贡献与胰腺炎发作相关的胰蛋白酶激活的这两种机制尚不清楚。解决在这个知识差距，我们提出了胰蛋白酶原激活的三种不同的情况。 1）在没有基因突变引起的胰蛋白酶原自身活化增加，组织蛋白酶B可以诱导显着癌性胰蛋白酶激活，而不会影响胰腺炎的严重程度。（2）如果遗传突变胰蛋白酶原中度增加自动激活，实验诱导的胰腺炎的严重程度将取决于组织蛋白酶B介导的胰蛋白酶原活化的程度。（3）最后，如果遗传变化这会导致强大的胰蛋白酶原自动活化，发作年龄和发起胰腺炎的严重程度是由组织蛋白酶B介导的胰蛋白酶原激活确定。在此赠款建议中，我们将测试每一个这三个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理提供新的机械洞察力胰腺炎，并将促进新型热和预防方法的发展。