| Chronic pancreatitis is a progressive inflammatory process ultimately resulting in irreversible damage to the pancreas with exocrine and endocrine dysfunction. It is relatively frequent with an estimated prevalence of 50-75 cases per 100,000 inhabitants. Most patients with chronic pancreatitis require intensive medical care because of relapsing attacks of incapacitating abdominal pain. Although alcohol abuse is regarded as a substantial risk factor, the actual cause of chronic pancreatitis remains unknown. Trypsinogen is the central molecule responsible for the activation of all other pancreatic digestive zymogens. Mutations in the trypsinogen gene have been detected in families with hereditary forms of pancreatitis. While these mutations might explain the phenotype in some patients, the underlying molecular defect in the large majority of patients with chronic pancreatitis remains unknown. Apart from these germline mutations, functional defects or improper cellular compartmentalisation of the trypsinogen molecule or one of its inhibitors might also play a pathogenetic role. The overall aim of this application is (1) to identify the molecular defects in chronic pancreatitis and the pathophysiological consequences observed, (2) to explore the cellular mechanism as to how these molecules can elicit pancreatitis. The key objectives of the application can then be specified as follows: (a) define the molecular defects in chronic pancreatitis and establish the clinical correlates; (b) elucidate the functional consequences of mutations and (c) investigate the molecular mechanisms that determine the cellular localisation and trafficking of trypsinogen and/or its inhibitors. Elucidation of the genetic defect and the pathophysiological changes observed, affords understanding of this, so far, enigmatic disorder and opens the door for new therapeutic avenues. |
