Role of trypsinogen sulfation in alcoholic pancreatitis

描述(申请人提供)：这项探索性拨款的主要目的是调查酒精性胰腺炎是由胰酶原过早激活引起的假说，这是胰酶原翻译后修饰改变的结果。我们认为，酒精可能通过影响胰酶原分子表面酪氨酰侧链的翻译后硫酸盐化程度来改变胰酶原的功能性质。这种异常的胰酶原会导致 胰酶原激活增强或胰酶稳定性增强。这一假说得到了我们最近的知识的支持，即阳离子胰酶原中的遗传性胰腺炎相关突变会导致非典型的胰酶原分子，表现出更快的激活或更高的稳定性。我们认为，乙醇诱导的人胰酶原翻译后硫酸盐化的变化可能模仿某些遗传性胰腺炎相关突变的影响，并导致酒精性胰腺炎。我们的主要目标是(1)表征人类胰酶原的翻译后修饰基团；(2)检测人类胰酶原翻译后硫酸盐化的功能后果；(3)开发一种简便的方法来监测胰酶原翻译后硫酸盐化的程度，以及(4)研究酒精性和特发性慢性胰腺炎中胰蛋白酶原硫酸盐化是如何改变的。

DESCRIPTION (provided by applicant): The main objective of this exploratory grant is to investigate the hypothesis that alcoholic pancreatitis is caused by premature intrapancreatic trypsinogen activation, as a result of altered post-translational modification of trypsinogen. We propose that alcohol might alter the functional properties of trypsin(ogen) by affecting the extent of post-translational sulfation of a tyrosyl sidechain on the surface of the trypsinogen molecule. This aberrant trypsinogen would result in enhanced trypsinogen activation or increased trypsin stability in the pancreas. This hypothesis draws support from our recent knowledge that hereditary pancreatitis-associated mutations in the cationic trypsinogen result in atypical trypsinogen molecules, which exhibit faster activation or higher stability. We propose that ethanol-induced changes in the post-translational sulfation of human trypsinogens might mimic the effects of certain hereditary pancreatitis-associated mutations, and cause alcoholic pancreatitis. Our major specific aims are to (1) characterize the posttranslational modifying group on human trypsinogens; (2) examine the functional consequences of post-translational sulfation of human trypsinogens; (3) develop a facile method to monitor the extent of post-translational sulfation of trypsinogens, and (4) investigate how trypsinogen sulfation is altered in alcoholic and idiopathic chronic pancreatitis.