Molecular Mechanisms of Acute Pancreatitis

急性胰腺炎的分子机制

• 批准号: 7800455
• 负责人: Craig D Logsdon
• 金额: $ 30.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800455
• 关键词: Acinar Cell; Acinus organ component; Acute; Adenovirus Vector; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Cell Survival; Cells; Complement; Development; Disease; Dominant-Negative Mutation; Duct (organ) structure; Event; Fibrosis; Gene Expression; Generations; Genes; Genetic Recombination; Growth; Human; In Vitro; Inflammatory; Injury; Knowledge; Laboratories; Lead; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; NF-kappa B; Natural regeneration; Necrosis; Pancreas; Pancreatitis; Prostaglandin Production; Research Personnel; Rodent; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Transcriptional Regulation; Transgenic Animals; Transgenic Mice; Trypsin; Viral Vector; Work; acute pancreatitis; base; cell injury; chronic pancreatitis; clinically relevant; effective therapy; human disease; improved; in vivo; injured; insight; mortality; mouse model; mutant; novel; p65; programs; recombinase; response; stellate cell; tool

DESCRIPTION (provided by applicant): 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 NF?B signaling pathway. Despite much evidence that NF?B is a critical mediator of pancreatitis, many important questions remain about its specific actions in the disease. We will directly examine the role of NF?B by regulating the expression of molecules that will either activate (p65/relA over-expression) or inhibit (l??-? deletion or I?B? expression) NF?B specifically in pancreatic acinar cells. We will test several mechanistic hypotheses concerning the roles of acinar cell NF?B 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.

描述（由申请人提供）：胰腺炎与显著的发病率和死亡率相关。不幸的是，目前还没有有效的治疗方法来治疗这种疾病。这主要是因为决定这种疾病严重程度的分子机制仍然知之甚少。由于缺乏明确的动物模型，对这些机制的了解受到阻碍。在目前的建议中，我们将利用新的转基因动物模型，我们最近开发的基础上腺泡细胞特异性表达的他莫昔芬调节Cre重组酶，用于激活或删除基因，直接调节胰腺炎的严重程度。这些是胰腺炎的第一个动物模型，其中分子起始事件被明确定义。本提案的总体目标是使用这些独特的模型来测试特定的机制假设。具体目标#1涉及NF？B信号通路。尽管有很多证据表明，NF？B是胰腺炎的关键介质，关于其在疾病中的具体作用仍存在许多重要问题。我们将直接检查NF的作用？B通过调节激活（p65/relA过表达）或抑制（p65/relA过表达）的分子的表达来实现。删除还是我？B？表达式）NF？B在胰腺腺泡细胞中特异性表达。我们将测试几个机制假设的作用，腺泡细胞NF？急性胰腺炎相关炎症级联反应中的B活化、腺泡细胞凋亡和坏死以及胰腺再生。具体目标#2是基于胰腺腺泡细胞中突变型活性K-ras（G12 V）的调节表达。虽然活化的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腺泡细胞的急剧损失和类似于人类慢性胰腺炎的大量纤维化。我们将利用这种独特的动物模型，以确定特定的分子机制，K-ras活性导致腺泡细胞损伤和影响星状细胞产生纤维化。为了补充转基因小鼠的研究并确保所研究的机制与人类疾病相关，我们还将使用病毒载体在人类和啮齿动物腺泡细胞中表达基因进行体外研究。这些研究将共同提供对急性胰腺炎机制的见解，这在以前是不可能的，并可能导致改善治疗。