Calcineurin in pancreatitis

 描述（由申请人提供）：胰腺炎是一种主要的危及生命的健康问题。胰腺炎的一个重要医源性原因发生在称为内镜逆行胰胆管造影术（ERCP）的常见GI程序之后。尽管最近的胰管支架植入术和抗炎预防措施改善了ERCP术后胰腺炎（PEP）的结局，但PEP仍然是一个令人生畏的问题，NIDDK认为这是一种值得关注的疾病。此外，PEP的分子机制仍然难以捉摸。我们的实验室积极研究异常Ca 2+信号在胰腺炎发病机制中的作用。在初步数据中，我们已经确定，在ERCP期间灌注到胰胆管中的放射性造影剂（RC）触发胰腺腺泡细胞中强有力的胞质Ca 2+信号，并诱导Ca 2+磷酸酶钙调神经磷酸酶（Cn）的激活。因此，该提案的总体目标是研究Ca 2+和Cn在介导PEP中的作用，重点是RC暴露。我们的总体假设是PEP的主要机制是诱导异常的胰腺腺泡细胞Ca 2+信号和激活Cn。我们的具体目的是（目的1）研究RC暴露于胰腺（1a）如何诱导腺泡细胞异常Ca 2+信号和（1B）如何激活Cn;（目的2）研究RC激活Cn是否是诱导（2a）NF- κB炎症信号和（2B）胰腺损伤的关键;和（目的3）确定（3a）腺泡细胞是否是PEP期间Cn活化的关键位点和（3b）将Cn抑制剂靶向递送至胰腺是否将防止PEP。我们相信，该提案将提供一个坚实的基础，以检查Ca 2+和Cn通路在介导PEP和胰腺炎的作用，预期的目标是设计预防PEP和潜在的治疗胰腺炎与Cn抑制剂的靶向治疗。

 DESCRIPTION (provided by applicant): Pancreatitis is a major life-threatening health problem. An important iatrogenic cause of pancreatitis occurs after a common GI procedure called an endoscopic retrograde cholangiopancreatography (ERCP). Although recent pancreatic duct stenting and anti-inflammatory prophylaxis have improved post-ERCP pancreatitis (PEP) outcomes, PEP is still a formidable problem that is recognized by NIDDK as a disease of interest. Furthermore, the molecular mechanisms underlying PEP remain elusive. Our lab actively examines the role of aberrant Ca2+ signals in the pathogenesis of pancreatitis. In preliminary data, we have identified that the radiocontrast (RC) instilled into the pancreatico-biliary ducts during ERCP triggers robust cytosolic Ca2+ signals in pancreatic acinar cells and induces the activation of the Ca2+ phosphatase calcineurin (Cn). Thus the overall goal of the proposal is to examine the role of Ca2+ and Cn in mediating PEP, with emphasis on RC exposure. Our overarching hypothesis is that a primary mechanism for PEP is the induction of aberrant pancreatic acinar cell Ca2+ signals and activation of Cn. Our specific aims are (Aim 1) to examine how RC exposure to the pancreas (1a) induces aberrant acinar cell Ca2+ signals and (1b) activates Cn; (Aim 2) to examine whether Cn activation by RC is critical to inducing (2a) NF- κB inflammatory signals and (2b) pancreatic injury; and (Aim 3) to determine (3a) whether acinar cells are a critical site of Cn activation during PEP and (3b) whether targeted delivery of Cn inhibitors to the pancreas will prevent PEP. We believe that the proposal will provide a solid basis to examine the role of Ca2+ and Cn pathways in mediating PEP and pancreatitis, with the anticipated goal to devise targeted therapies for preventing PEP and potentially treating pancreatitis with Cn inhibitors.