Susceptibility mechanism in alcoholic pancreatitis

酒精性胰腺炎的易感机制

• 批准号: 7038169
• 负责人: HERBERT Young GAISANO
• 金额: $ 12.83万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038169
• 关键词: acinar cell; alcoholism /alcohol abuse; cell membrane; cholecystokinin; disease /disorder etiology; disease /disorder model; disease /disorder proneness /risk; ethanol; exocytosis; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; membrane proteins; molecular /cellular imaging; pancreatitis; pathologic process; protein kinase C; protein structure function

DESCRIPTION (provided by applicant): Much is known about the downstream events leading to experimental acute pancreatitis. However, neither acute nor chronic alcohol treatment could independently induce these downstream events to actually cause damage to the exocrine pancreas! The current consensus is that alcohol induces undefined upstream 'susceptibility' factors, which in the presence of downstream triggering events, then lead to pancreatic injury. The precise susceptibility factor(s) activated by alcohol in exocrine pancreas is however unknown. Our long-term goal is to elucidate the underlying alcohol-induced susceptibility factors predisposing to pancreatitis. Using a fluorescent imaging assays, we visualized in real time that supramaximal CCK stimulation redirected exocytosis normally occurring at the apical plasma membrane (PM) surface to the basolateral surface. The underlying molecular mechanism of the basolateral exocytosis involves a complex of SNARE proteins: Munc18c/Syn-4/SNAP23/VAMP, whereby high CCK caused Munc18c to dissociate from Syntaxin4 on the basolateral PM. This relieves basolateral PM-Syn-4 to then bind SNAP-23 and zymogen granule VAMP to form the SNARE exocytic complex which consummates exocytosis. This mechanism also played a role in supramaximal CCK-induced rat acute pancreatitis. We now HYPOTHESIZE that alcohol participates in evoking excess exocytosis at the basolateral PM, by inducing Munc18c to become displaced from Syn-4 at the basolateral PM into the cytosol. This susceptibility mechanism in part via PKC pathways induced by alcohol renders the basolateral PM surface receptive to pathological exocytosis, which we will examine in Aim 1. The resulting excess in ectopic release of digestive enzymes into the interstitial space, when not efficiently cleared by the micro-circulation, become activated to cause pancreatic tissue injury which we will examine in an alcohol diet pancreatitis model in Aim 2. Significance: These actions of alcohol on pancreatic acinar PM-Munc18c may be the 'sentinel' event that initiates the role of alcohol in pancreatic injury, and which could be therapeutically targeted.

描述（由申请人提供）：关于导致实验性急性胰腺炎的下游事件知之甚少。但是，急性和慢性酒精治疗都无法独立诱导这些下游事件，以实际损害外分泌胰腺！目前的共识是，酒精会诱导上游“敏感性”因素，在下游触发事件的情况下，然后导致胰腺损伤。但是，尚不清楚由酒精在外分泌胰腺中激活的精确易感因子。我们的长期目标是阐明易感胰腺炎的基本酒精引起的敏感性因素。 使用荧光成像测定法，我们实时可视化，可刺激刺激重定向胞吐作用，通常发生在基底外侧表面的顶端质膜（PM）表面。基底外侧外胞胞菌病的潜在分子机制涉及一系列的snare蛋白：munc18c/syn-4/snap23/vamp，因此高CCK导致munc18c在基底外侧PM上与syntaxin4分离。这样可以缓解基底外侧PM-Syn-4，然后结合SNAP-23和Zymogen颗粒鞋面，形成造成胞吐作用的圈型胞外复合物。该机制在CCK诱导的大鼠急性胰腺炎中也发挥了作用。 现在，我们假设酒精参与诱发基底外侧PM的过量胞吐作用，通过诱导Munc18c从基底外侧PM的Syn-4移动到细胞质中。酒精诱导的PKC途径的部分这种敏感性机制使基底外侧PM表面接受病理胞外生命，我们将在目标1中检查，这是AIM 1。导致的分解释放过多的消化酶向间质空间中的分解释放过多，当时无法通过pantiit Inties进行pantiit Is procantiit Inifit Initiviit Is to pantiit Is to partiit Is to pantiit Is to pantiit Is to pantiit procanties。 2。意义：酒精对胰腺粉刺PM-MUNC18C的行为可能是启动酒精在胰腺损伤中作用的“前哨”事件，并且可以针对治疗。