Alcohol Induced Chronic Pancreatitis

酒精诱发的慢性胰腺炎

• 批准号: 8215516
• 负责人: Craig D Logsdon
• 金额: $ 35.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215516
• 关键词: Acinar Cell; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Disease Models; Animal Feed; Animal Model; Animals; Apoptosis; Apoptotic; Autophagocytosis; Biological Factors; Breeding; CCAAT-Enhancer-Binding Protein-alpha; Caerulein; Cell Death; Cells; Cellular Stress; Cholecystokinin; Chronic; Data; Development; Diet; Disease; Down-Regulation; Ethanol; Genetic; Goals; Heterozygote; Human; Inflammation; Inflammatory Response; Inherited; Injury; Lead; Metallothionein; Modeling; Mus; Mutation; Necrosis; Pancreas; Pancreatic Diseases; Pancreatitis; Pathology; Play; Predisposition; Research Personnel; Rodent; Role; Severity of illness; Stress; Supplementation; Testing; Time; Translations; Trypsin; Trypsinogen; acute pancreatitis; alcohol abuse therapy; alcohol effect; alcoholic chronic pancreatitis; chronic pancreatitis; factor C; feeding; injured; mouse model; mutant; novel; response; transcription factor

DESCRIPTION (provided by applicant): Alcohol abuse is associated with at least 70% of cases of chronic pancreatitis (CP) and 40% of acute pancreatitis. Yet, only a small percentage of those who abuse alcohol develop pancreatic disease. Clearly there are other biological factors which predispose to the development of pancreatitis and alcohol abuse is acting as a triggering mechanism. But what are these factors? Unfortunately, to date no animal model has been developed that recapitulates alcohol related CP. Therefore, it has been difficult to make progress against this disease. However, we have recently developed two novel mouse models which are sensitive to alcohol and develop severe CP without the need for additional insults. The models involve regulated pancreatic acinar cell specific expression of mutant trypsin molecules. One is an experimental construct that becomes activated upon translation (called Trypon mice). The other involves expression of the R122H trypsinogen mutant (called R122H mice) which is associated with hereditary pancreatitis. Neither of these mutant trypsin molecules induces pancreatitis or any obvious perturbations when expressed as a heterozygote. However, when R122G or Trypon mice are fed an alcohol diet; they develop profound CP. These data support a hypothesis that alcohol sensitizes the pancreas to factors that affect trypsin activation or protection from active trypsin. The goal of this proposal is to understand the mechanisms involved in these effects by pursuing three specific aims. Aim #1: Determine whether acute or chronic intake of alcohol is necessary to generate CP in mice expressing mutant trypsin. Alcohol has multiple effects and the effects of acute and chronic alcohol are often opposite. It will be important to understand whether alcohol is required in the short or long term to generate chronic pancreatitis in this model. We will also determine the effects of alcohol on trypsin activity to assess whether trypsin itself is the key mechanism. Together these studies will provide important basic information about the model. Aim #2: We will determine the form(s) of acinar cell death initiated in these animals by ethanol. We hypothesize that alcohol perturbs normal cellular mechanisms such that intracellular trypsin induces necrosis in acinar cells. We will also examine whether autophagy is involved in the effects of ethanol in this model. Aim #3. Determine the role of metallothionein (MT) in the development of CP in alcohol treated mice expressing mutant trypsin. We have previously found that alcohol feeding causes a down-regulation of MT, which normally plays a protective role in acute pancreatitis. To understand the role of MT in alcohol related CP we will examine the effects of mutant trypsin expression in mice with high (Zn treated) or low (MT deficient) levels of MT. We will also investigate the mechanisms of alcohol reduction of MT expression. Together these novel models and approaches will provide important new information about the relationship between alcohol and pancreatic disease. PUBLIC HEALTH RELEVANCE: The development of new treatments for alcohol related pancreatic disease had been hindered by the lack of physiologically relevant animal models. We have developed for the first time an animal model with a modified genetic background that develops alcohol dependent chronic pancreatitis without the need for additional injurious treatments. This new model will provide an opportunity to discover important new details about the role of alcohol in pancreatic disease.

描述（由申请人提供）：至少 70% 的慢性胰腺炎 (CP) 病例和 40% 的急性胰腺炎病例与酗酒有关。然而，只有一小部分酗酒者会患上胰腺疾病。显然，还有其他生物因素导致胰腺炎的发生，而酗酒则是一种触发机制。但这些因素是什么？不幸的是，迄今为止，尚未开发出能够概括酒精相关性脑瘫的动物模型。因此，针对这种疾病很难取得进展。然而，我们最近开发了两种新型小鼠模型，它们对酒精敏感，无需额外的刺激即可发展出严重的脑瘫。该模型涉及突变胰蛋白酶分子受调节的胰腺腺泡细胞特异性表达。一种是翻译后被激活的实验结构（称为 Trypon 小鼠）。另一种涉及与遗传性胰腺炎相关的 R122H 胰蛋白酶原突变体（称为 R122H 小鼠）的表达。当这些突变胰蛋白酶分子以杂合子表达时，都不会诱发胰腺炎或任何明显的干扰。然而，当 R122G 或 Trypon 小鼠喂食酒精饮食时；他们发展出深厚的CP。这些数据支持这样的假设：酒精使胰腺对影响胰蛋白酶激活或免受活性胰蛋白酶保护的因素敏感。该提案的目标是通过追求三个具体目标来了解这些影响所涉及的机制。目标#1：确定在表达突变胰蛋白酶的小鼠中是否需要急性或慢性摄入酒精来产生 CP。酒精有多种作用，急性和慢性酒精的作用往往是相反的。重要的是要了解在该模型中是否需要短期或长期饮酒才能产生慢性胰腺炎。我们还将确定酒精对胰蛋白酶活性的影响，以评估胰蛋白酶本身是否是关键机制。这些研究将共同​​提供有关该模型的重要基本信息。目标#2：我们将确定乙醇在这些动物中引发的腺泡细胞死亡的形式。我们假设酒精扰乱正常的细胞机制，使得细胞内胰蛋白酶诱导腺泡细胞坏死。我们还将检查自噬是否参与该模型中乙醇的作用。目标#3。确定金属硫蛋白 (MT) 在表达突变胰蛋白酶的酒精处理小鼠 CP 发展中的作用。我们之前发现，饮酒会导致 MT 下调，而 MT 通常在急性胰腺炎中发挥保护作用。为了了解 MT 在酒精相关 CP 中的作用，我们将检查突变胰蛋白酶表达对高（锌处理）或低（MT 缺乏）水平 MT 的小鼠的影响。我们还将研究酒精降低 MT 表达的机制。这些新模型和方法将共同提供有关酒精与胰腺疾病之间关系的重要新信息。 公共卫生相关性：由于缺乏生理相关的动物模型，酒精相关胰腺疾病新疗法的开发受到阻碍。我们首次开发了一种具有改良遗传背景的动物模型，该模型无需额外的有害治疗即可患上酒精依赖性慢性胰腺炎。这个新模型将为发现有关酒精在胰腺疾病中的作用的重要新细节提供机会。