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

描述（由申请人提供）： 我是一名对急性胰腺炎（AP）的分子和细胞机制感兴趣的医生科学家。我的短期职业目标是使用CF的小鼠模型来研究为什么患有非典型CF的人会发生复发性AP，这些发现可能会导致疾病预防和有效治疗。该项目由Owyang博士和我的科学顾问委员会指导，并提供职业发展计划，以确保在3-4年内成功获得R 01资助和发展为独立研究者。 CFTR基因突变见于17-38%的特发性复发性AP患者，这是一种非典型CF表型。初步数据提供了新的发现，即用AP诱导的CF小鼠发生与抗凋亡腺泡细胞反应和旺盛的胰腺炎症相关的更严重的损伤。由于胰腺腺泡细胞表达CFTR是弱的，功能意义可疑，我研究了腺泡外触发器来解释腺泡抗凋亡表型。抗凋亡腺泡Na+/H+交换器（NHE-1）的表达和功能是重要的，因为在CF小鼠和人CF中，腺泡间空间和小管内腔是酸性的，并且细胞外酸性激活NHE-1。初步研究表明，NHE-1蛋白在CF小鼠胰腺中过表达，野生型小鼠中的NHE-1药理学抑制或基因缺失降低了AP的严重程度，并与腺泡细胞凋亡标志物增加相关。我假设CF小鼠对更严重AP和非典型人类CF对复发AP的易感性归因于胰腺腺泡细胞对细胞凋亡的抵抗，因为腺泡NHE-1激活。我建议1）确定CF腺泡细胞对抗凋亡、促炎表型的个体贡献; 2）描绘AP期间CF小鼠中负责抗凋亡表型的促凋亡蛋白和抗凋亡蛋白; 3）确定AP的严重程度是否通过抑制或删除NHE-1而减弱并与凋亡增加偶联。 急性胰腺炎（AP）与相当大的发病率和死亡率相关，在美国每年导致3200例死亡和30万例住院治疗，花费超过20亿美元。对AP的病理生理学的理解是不完整的，缺乏治疗方法。这项研究可能会深入了解AP和CF的发病机制，并有助于产生新的治疗方法。

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.