Molecular Mechanisms of Acute Pancreatitis

胰腺炎与显著的发病率和死亡率相关。不幸的是，目前 没有有效的治疗方法。这在很大程度上是因为 确定这种疾病的严重程度仍然知之甚少。了解这些机制 由于缺乏明确的动物模型而受到阻碍。在目前的提案中，我们将 利用我们最近开发的基于腺泡细胞的新型转基因动物模型， 特异性表达他莫昔芬调节的Cre重组酶，所述Cre重组酶用于激活或缺失 直接调节胰腺炎严重程度的基因。这是第一个胰腺炎的动物模型 其中分子起始事件被清楚地定义。本提案的总体目标是 使用这些独特的模型测试特定的机械假设。具体目标#1涉及 调节NFxB信号通路组分的表达。尽管有很多证据表明， NFxfi是胰腺炎的关键介质，关于其特异性的许多重要问题仍然存在。 在疾病中的行动。我们将通过调节NFxfi的表达来直接检查NFxfi的作用。 将激活（p65/relA过表达）或抑制（lkk| 3缺失或kBa 表达）NFicB特异性地在胰腺腺泡细胞中。我们将测试几种机械 关于腺泡细胞NF κ B活化在炎症级联反应中的作用的假说， 细胞凋亡和坏死以及与急性胰腺炎相关的胰腺再生。 具体目标#2是基于胰腺腺泡中突变型活性K-ras（G12 V）的调节表达 细胞虽然激活的K-ras通常与胰腺癌相关，但我们观察到， 其在转基因动物胰腺内腺泡细胞中的表达导致了胰腺癌细胞的显著丧失。 腺泡细胞和丰富的纤维化类似人类慢性胰腺炎。我们会利用这个 独特的动物模型，以确定K-ras活性导致的特定分子机制 腺泡细胞损伤并影响星状细胞产生纤维化。为了补充 转基因小鼠，并确保正在研究的机制与人类相关， 此外，我们亦会进行体外研究，利用病毒载体在人体内表达基因， 啮齿动物腺泡细胞。这些研究将共同提供对急性脑梗死机制的见解。 胰腺炎，以前没有可能的，这可能导致改善治疗。

Pancreatitis is associated with significant morbidity and mortality. Unfortunately, there are currently no effective therapies for this disease. This is largely because the molecular mechanisms that determine the severity of this disease remain poorly understood. Knowledge of these mechanisms has been hampered by the lack of well-defined animal models. In the current proposal, we will utilize novel transgenic animal models that we have recently developed based on acinar cell specific expression of a tamoxifen-regulated Cre recombinase that is used to activate or delete genes that directly regulate pancreatitis severity. These are the first animal models of pancreatitis in which the molecular initiating events are clearly defined. The overall aims of this proposal are to test specific mechanistic hypotheses using these unique models. Specific aim #1 involves the regulated expression of components of the NFxB signaling pathway. Despite much evidence that NFxfi is a critical mediator of pancreatitis, many important questions remain about its specific actions in the disease. We will directly examine the role of NFxfi by regulating the expression of molecules that will either activate (p65/relA over-expression) or inhibit (lkk|3 deletion or kBa expression) NFicB specifically in pancreatic acinar cells. We will test several mechanistic hypotheses concerning the roles of acinar cell NFicB activation in the inflammatory cascade, acinar cell apoptosis and necrosis, and pancreatic regeneration associated with acute pancreatitis. Specific aim #2 is based on regulated expression of mutant active K-ras(G12V) in pancreatic acinar cells. While activated K-ras is generally associated with pancreatic cancer, we have observed that its expression in acinar cells within the pancreas of transgenic animals leads to a dramatic loss of acinar cells and abundant fibrosis resembling human chronic pancreatitis. We will utilize this unique animal model to identify the specific molecular mechanisms whereby K-ras activity causes acinar cell damage and influences stellate cells to produce fibrosis. To complement the studies in transgenic mice and to insure that the mechanisms being investigated are relevant to human disease, we will also conduct studies in vitro using viral vectors to express genes in human and rodent acinar cells. Together these studies will provide insights into the mechanisms of acute pancreatitis that have not previously been possible and which may lead to improved therapies.