Murine Model for Alcohol Dependent Chronic Pancreatitis

酒精依赖性慢性胰腺炎小鼠模型

• 批准号: 6972944
• 负责人: GEORGE PERIDES
• 金额: $ 23.43万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972944
• 关键词: SDS polyacrylamide gel electrophoresis; actins; alcoholism /alcohol abuse; cell proliferation; collagen; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; ethanol; extracellular matrix proteins; fibrosis; gene expression; genetically modified animals; immunocytochemistry; laboratory mouse; metalloendopeptidases; pancreatitis; phosphorylation; polymerase chain reaction; posttranslational modifications; protein biosynthesis; statistics /biometry; tissue inhibitor of metalloproteinases; toxicant interaction; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Most patients develop chronic pancreatitis after prolonged ethanol abuse. It is generally believed that ethanol contributes to the evolution of pancreatitis by sensitizing the gland to injury by other potentially harmful factors, either genetic (e.g. CFTR mutations) or acquired (e.g. infectious agents, drugs of abuse, etc.), This relationship between ethanol abuse and chronic pancreatitis has complicated studies focusing on the mechanisms responsible for chronic pancreatitis and convinced most investigators that successful studies directed at elucidating the early events in clinical chronic pancreatitis will depend upon the development of good experimental models of the disease. Ideally, the disease in those models should resemble :he clinical disease morphologically and it should be dependent upon exposure to ethanol. Furthermore, it would be helpful if the model was elicited in mice since this would allow investigators to exploit the abundance of genetically altered mouse strains in mechanistic studies. To date, unfortunately, no such model has been developed. Rather, the models most frequently employed involve either (a) exposing ethanol fed rats to the combined effects of acute inflammation and administration of cyclosporine A (b) subjecting non-ethanol fed mice to repeated episodes of acute pancreatic inflammation or (c) exposing isolated pancreatic cells to pancreatitis-related agents under in-vitro conditions. We have recently obtained preliminary evidence that mice fed an ethanol-containing diet for six weeks and then subjected to repeated episodes of non-ethanol induced acute pancreatitis develop changes that are characteristic of chronic pancreatitis i.e. pancreatic fibrosis, and intra-pancreatic deposition of collagen. The current R21 proposal will build upon these preliminary observations by pursuing the following specific aims: (1) to determine, at the protein or enzyme activity level, if ethanol triggers a pro-fibrogenetic alteration in matrix remodeling enzymes; (2) to determine whether it is the exposure to ethanol alone, the repeated episodes of inflammation alone, or the combination of these two events that leads to pancreatic stellate cell activation and collagen synthesis during chronic pancreatitis; and (3) to demonstrate the utility of this model by using it, along with genetically modified mouse strains, in studies that examine the role of matrix-remodeling enzymes in the evolution of ethanol-dependent chronic pancreatitis.

描述（由申请人提供）：大多数患者在长期滥用乙醇后会出现慢性胰腺炎。人们普遍认为，乙醇通过使腺体对其他潜在有害因素（例如CFTR突变）或获得的其他潜在有害因素的伤害敏感或获得（例如，感染因素，滥用药物等），对大多数研究乙醇滥用和慢性panc posection的研究对机械的研究之间的这种关系，这是造成胰腺炎的进化。旨在阐明临床慢性胰腺炎的早期事件将取决于疾病的良好实验模型的发展。理想情况下，这些模型中的疾病应该类似于：他在形态上临床疾病，应取决于暴露于乙醇。此外，如果在小鼠中引起该模型，这将是有帮助的，因为这将使研究人员在机械研究中利用大量遗传变化的小鼠菌株的丰度。迄今为止，不幸的是，尚未开发此类模型。相反，最常使用的模型涉及（a）将乙醇喂养到急性炎症的综合作用以及对非乙醇喂养小鼠的抗孢子孢菌A（b）的施用，以在急性胰腺炎症中重复发作，或者（c）在胰岛炎下对胰腺炎的胰腺炎性细胞，对胰腺炎侵害性炎症性疾病，以下是伴有胰腺炎的条件。我们最近获得了初步证据，表明小鼠喂养含有乙醇的饮食六周，然后经过非乙醇诱导的急性急性胰腺炎的重复发作，发生了变化的变化，这些变化是慢性胰腺炎的特征，即胰腺纤维化，以及胶原蛋白的胰腺内pep依。当前的R21提案将通过追求以下特定目的来基于这些初步观察：（1）如果乙醇触发基质重塑酶的促纤维化改变，则确定，以蛋白质或酶活性水平确定； （2）确定它是否是单独暴露于乙醇，单独炎症的重复发作，或者是这两个事件的组合，这些事件导致胰腺胰腺炎期间导致胰腺星状细胞活化和胶原蛋白合成； （3）在研究基质复制酶在乙醇依赖性慢性胰腺炎进化中的作用的研究中，通过使用基因修饰的小鼠菌株来证明该模型的实用性。