Effects of Ethanol on Pancreas Regeneration

描述(申请人提供)：酒精滥用通常与急性胰腺炎有关，但酒精使胰腺敏感或使其易于受损的机制尚不清楚。急性胰腺炎的特征是胰腺腺泡细胞的炎症和损伤。根据临床观察和动物研究，通常认为，急性胰腺炎发作后，胰腺在12-14天内再生到其结构和功能的全部能力。胰腺和肝脏是发育相关的，两个器官都表达酒精脱氢酶和细胞色素P450 2E1。此外，酗酒与这两个器官的疾病有关。众所周知，酒精摄入会损害肝脏再生。因此，我们推测酒精摄入也会损害胰腺再生。在初步研究中，使用酒精喂养和柯萨奇病毒感染引起的胰腺损伤相结合的酒精性胰腺炎小鼠模型，我们研究了这种可能性。根据组织学和酶学数据，我们的初步结果支持酒精喂养损害胰腺再生的建议。已有研究表明，胰腺的再生需要特定生长因子的紧密协调作用。研究表明，酒精摄入可以改变生长因子的表达和信号传递。因此，我们的假设是，酒精摄入会损害胰腺在严重损伤后再生到充分的结构和功能能力的能力，这种损害是由特定生长因子在时间或数量上的异常表达所介导的。为了验证这一假说，我们提出了以下具体目标：1)进一步表征病毒诱导的胰腺炎后乙醇诱导的胰腺再生损伤；2)确定乙醇诱导的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重要信息，并为未来的研究奠定基础，以确定慢性乙醇摄入影响并导致这种乙醇介导的再生障碍的分子和生化途径。

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.