Role of CCK Receptor in Acute Pancreatitis Pathogenesis

CCK受体在急性胰腺炎发病机制中的作用

• 批准号: 6825740
• 负责人: ISAAC SAMUEL
• 金额: $ 12.61万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825740
• 关键词: Role; CCK; Receptor; Acute; Pancreatitis

EXCEED THE SPACE PROVIDED. Acute pancreatitis is a common disease with significant morbidity and mortality but no specific treatment is available as the pathogenic mechanisms are not known. The purpose of this research proposal is to elucidate early events in pathogenesis of gallstone-induced acute pancreatitis. We use the rat model of bile- pancreatic duct ligation-induced acute pancreatitis as an experimental corollary. Bile-pancreatic juice exclusion from gut causes feedback exocrine pancreatic stimulation via cholecystokinin-A receptor (CCK- AR) mechanisms. The role of the CCK-AR in disease pathogenesis is not known. Our preliminary studies provide the first evidence that CCK-AR mediated pancreatic acinar cell hyperstimulation plays a contributory role in disease pathogenesis and that induction of CCK-AR occurs within one hour of duct ligation. We hypothesize that pathological amplification of CCK-AR mediated signal transduction exacerbates disease pathogenesis. We propose experiments to test this hypothesis and pursue these specific aims: 1) Characterize the role of the CCK-AR in duct occlusion-induced acute pancreatitis pathogenesis. 2) Characterize the expression and regulation of the CCK-AR in duct occlusion-induced acute pancreatitis. 3) Characterize the CCK-AR mediated signal transduction pathway in duct occlusion-induced acute pancreatitis. Competitive binding assays with radiolabeled ligand will be done to study receptor number, specificity, and affinity. Receptor sensitivity and activity will be determined by measuring downstream signals (cyclic AMP, inositol phosphate). Differences between the induced and native receptor will be determined both in terms of altered functional characteristics and perturbations in intracellular signal transduction pathways. The possibility that promiscuous G-protein coupling in acute pancreatitis could drastically increase CCK-AR affinity and also perpetuate a grossly amplified intracellular signal may have profound implications in mechanisms of disease pathogenesis. An innovative feature of this proposal is the use of an original surgical model, "The Donor Rat Model", that provides a unique opportunity to investigate disease pathogenesis. The significance and health-relatedness of this research endeavor is its ultimate goal to elucidate mechanisms of disease pathogenesis that hopefully provide the rationale to base new treatment protocols intended to reduce the morbidity and mortality of acute pancreatitis. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。 急性胰腺炎是一种常见的疾病，具有显著的发病率和死亡率，但由于致病机制尚不清楚，因此没有特定的治疗方法。本研究的目的是阐明胆结石引起的急性胰腺炎发病机制的早期事件。我们使用胆胰管结扎诱导的大鼠急性胰腺炎模型作为实验推论。胆汁-胰液从肠道排出通过胆囊收缩素-A受体（CCK-AR）机制引起反馈性胰腺外分泌刺激。CCK-AR在疾病发病机制中的作用尚不清楚。我们的初步研究提供了第一个证据，CCK-AR介导的胰腺腺泡细胞过度刺激在疾病发病机制中起着促进作用，CCK-AR的诱导发生在导管结扎后1小时内。我们推测CCK-AR介导的信号转导的病理性放大加剧了疾病的发病机制。我们提出了实验来验证这一假设，并追求这些特定的目标：1）描述的作用，胆囊收缩素受体在导管闭塞引起的急性胰腺炎发病机制。2)研究胆管阻塞性急性胰腺炎中胆囊收缩素受体的表达和调节。3)描述胆管阻塞诱导的急性胰腺炎中CCK-AR介导的信号转导通路。将使用放射性标记配体进行竞争性结合试验，以研究受体数量、特异性和亲和力。通过测量下游信号（环AMP、磷酸肌醇）确定受体敏感性和活性。诱导和天然受体之间的差异将在细胞内信号转导途径的功能特性改变和扰动方面确定。在急性胰腺炎中，混杂的G蛋白偶联可能会显著增加CCK-AR亲和力，并使细胞内信号持续放大，这可能对疾病的发病机制有深远的影响。该提案的一个创新特征是使用原始手术模型“供体大鼠模型”，这为研究疾病发病机制提供了独特的机会。这项奋进的意义和健康相关性是其最终目标，以阐明疾病的发病机制，希望提供基础的新的治疗方案，旨在降低急性胰腺炎的发病率和死亡率的基本原理。性能现场=