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发展为慢性胰腺炎。人们普遍认为，乙醇通过使腺体对其他潜在有害因素（例如遗传因素（例如 CFTR 突变）或后天因素（例如传染源、滥用药物等）的损伤）敏感而促进胰腺炎的发展。乙醇之间的这种关系滥用和慢性胰腺炎使关注慢性胰腺炎机制的研究变得复杂，并使大多数研究人员相信，旨在阐明临床慢性胰腺炎早期事件的成功研究将取决于良好的实验模型的开发 疾病。理想情况下，这些模型中的疾病在形态上应该类似于临床疾病，并且应该依赖于乙醇的暴露。此外，如果在小鼠中引发该模型将会很有帮助，因为这将使研究人员能够在机制研究中利用大量转基因小鼠品系。不幸的是，迄今为止，还没有开发出这样的模型。相反，最常用的模型涉及（a）将乙醇喂养的大鼠暴露于急性炎症和给予环孢菌素A的联合作用（b）使非乙醇喂养的小鼠反复发作急性胰腺炎症，或（c）暴露于孤立的急性胰腺炎症。在体外条件下胰腺细胞与胰腺炎相关药物的关系。我们最近获得的初步证据表明，小鼠喂食含乙醇饮食六周，然后反复发作非乙醇诱发的急性胰腺炎，会出现慢性胰腺炎特征性的变化，即胰腺纤维化和胰腺内胶原沉积。目前的 R21 提案将建立在这些初步观察的基础上，追求以下具体目标：（1）在蛋白质或酶活性水平上确定乙醇是否会引发基质重塑酶的促纤维形成改变； (2) 确定慢性胰腺炎期间是否单独接触乙醇、单独炎症反复发作或这两种事件的组合导致胰腺星状细胞活化和胶原合成； (3) 通过使用该模型以及转基因小鼠品系，在研究基质重塑酶在乙醇依赖性慢性胰腺炎进化中的作用来证明该模型的实用性。