Effects of Ethanol on Pancreas Regeneration

描述（由申请人提供）：酒精滥用通常与急性胰腺炎有关，但乙醇致敏或易使胰腺损伤的机制尚不清楚。急性胰腺炎的特点是炎症和胰腺腺泡细胞损伤。根据临床观察和动物研究，人们普遍认为，急性胰腺炎发作后，胰腺在12-14天内再生到其完整的结构和功能。胰腺和肝脏是发育相关的，这两个器官都表达酒精脱氢酶和细胞色素P450 2E1。此外，酒精滥用与这两个器官的疾病有关。乙醇的消耗损害肝脏再生是公认的事实。因此，我们推测乙醇消耗也会损害胰腺再生。在初步研究中，我们使用酒精性胰腺炎小鼠模型，结合乙醇喂养和柯萨奇病毒感染引起的胰腺损伤，研究了这种可能性。根据组织学和酶学数据，我们的初步结果支持乙醇喂养损害胰腺再生的建议。研究表明，胰腺的再生需要特定生长因子紧密协调的作用。有充分的证据表明，乙醇消耗可以改变生长因子的表达和信号传导。因此，我们的假设是，乙醇消耗会损害胰腺在严重损伤后恢复其全部结构和功能能力的能力，而这种损害是由特定生长因子的异常时间或定量表达介导的。为了验证这一假设，我们提出了以下具体目标：1)进一步表征乙醇诱导的病毒性胰腺炎后胰腺再生损伤2)确定乙醇诱导胰腺再生损伤的分子机制。这些特定目标的完成将为乙醇对胰腺再生的影响提供新的和重要的信息，并为未来的研究奠定基础，以确定受慢性乙醇消耗影响的分子和生化途径，并导致乙醇介导的再生损伤。

DESCRIPTION (provided by applicant): Alcohol abuse is often associated with acute pancreatitis, but the mechanisms by which ethanol sensitizes or predisposes the pancreas to damage are not clear. Acute pancreatitis is characterized by inflammation and damage to the pancreatic acinar cells. It is generally thought, on the basis of clinical observations and animal studies, that, after an acute episode of pancreatitis, the pancreas regenerates to its full structural and functional capacity within 12-14 days. The pancreas and the liver are developmentally related and both organs express alcohol dehydrogenase and cytochrome P450 2E1. Additionally, alcohol abuse is associated with disease in both organs. It is well established that ethanol consumption impairs liver regeneration. Thus, we speculated that ethanol consumption would also impair pancreatic regeneration. In preliminary studies, using a murine model of alcoholic pancreatitis that combines ethanol feeding and pancreatic damage induced by coxsackievirus infection, we have investigated this possibility. On the basis of histologic and enzymatic data our preliminary results support the suggestion that ethanol feeding impairs pancreas regeneration. It has been shown that regeneration of the pancreas requires the tightly orchestrated, coordinated actions of specific growth factors. It is well documented that ethanol consumption can alter the expression and signaling of growth factors. Therefore, it is our hypothesis that ethanol consumption impairs the ability of the pancreas to regenerate to its full structural and functional capacity after severe damage, and this impairment is mediated by aberrant temporal or quantitative expression of specific growth factors. To test this hypothesis, we propose the following specific aims: 1) To further characterize the ethanol-induced impairment in pancreas regeneration after virally induced pancreatitis 2) To determine the molecular mechanisms responsible for the ethanolinduced impairment in pancreas regeneration. Completion of these specific aims will provide new and important information about the effects of ethanol on pancreatic regeneration, as well as forming the foundation for future studies to determine the molecular and biochemical pathways that are affected by chronic ethanol consumption and result in this ethanol-mediated impairment of regeneration.