Inflammatory response to pancreatitis in CF mice: sodium & impaired apoptosis

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DESCRIPTION (provided by applicant): I am a physician scientist interested in the molecular & cellular mechanisms of acute pancreatitis (AP). My short term career goal is to use a mouse model of CF to investigate why humans with atypical CF develop recurrent AP, findings which may lead to disease prevention & effective treatments. This project features mentorship by Dr. Owyang & my scientific advisory committee and a career development program which will ensure successful R01 funding & development as an independent investigator within 3-4 years. CFTR gene mutations are found in 17-38% of patients with idiopathic recurrent AP, an atypical CF phenotype. Preliminary data provided the novel findings that CF mice induced with AP develop more severe injury associated with an anti-apoptotic acinar cell response and exuberant pancreatic inflammation. Because pancreatic acinar cell expression of CFTR is weak and of doubtful functional significance, I investigated extra-acinar triggers to explain the acinar anti-apoptotic phenotype. Expression and function of the anti-apoptotic acinar Na+/H+ exchanger (NHE-1) is important because in both CF mice and human CF, the inter-acinar space and lumen of ductules is acidic, and extracellular acidity activates NHE-1. Preliminary studies showed that NHE-1 protein was overexpressed in CF mouse pancreas and that NHE-1 pharmacologic inhibition or genetic deletion in wild-type mice reduced the severity of AP and was associated with increased markers of acinar cell apoptosis. I hypothesized that the susceptibility of CF mice to more severe AP and atypical human CF to recurrent AP is attributable to pancreatic acinar cell resistance to apoptosis because of acinar NHE-1 activation. I propose 1) to determine the individual contribution of CF acinar cells to the anti-apoptotic, proinflammatory phenotype; 2) to delineate the pro- & anti-apoptotic proteins responsible for the anti-apoptotic phenotype in CF mice during AP; and 3) to determine whether the severity of AP is attenuated & coupled to increased apoptosis by inhibiting or deleting NHE-1. Acute pancreatitis (AP) is associated with considerable morbidity & mortality, leading to 3200 deaths and 300,000 hospitalizations annually in the USA, costing more than $2 billion. Understanding of the pathophysiology of AP is incomplete & therapies are lacking. The proposed study may provide insight into the pathogenesis of AP & CF & contribute to generation of novel therapies.