Alcohol Induced Chronic Pancreatitis

酒精诱发的慢性胰腺炎

• 批准号: 8997035
• 负责人: Craig D Logsdon
• 金额: $ 34.48万
• 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/8997035
• 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; Testing; Time; Translations; Trypsin; Trypsinogen; Zinc supplementation; 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.

描述(申请人提供)：酒精滥用与至少70%的慢性胰腺炎(CP)和40%的急性胰腺炎有关。然而，在酗酒者中，只有一小部分人会患上胰腺疾病。显然，还有其他生物因素容易导致胰腺炎的发展，而酗酒是触发机制。但这些因素是什么呢？不幸的是，到目前为止，还没有开发出概括酒精相关CP的动物模型。因此，在抗击这种疾病方面一直很难取得进展。然而，我们最近开发了两种新的小鼠模型，它们对酒精敏感，并在不需要额外侮辱的情况下发展为严重的CP。这些模型包括调节胰腺腺泡细胞特异性表达突变的胰蛋白酶分子。一种是一种实验性的结构，它在翻译后被激活(称为Trypon老鼠)。另一个涉及与遗传性胰腺炎有关的R122H胰酶原突变体(称为R122H小鼠)的表达。当以杂合子的形式表达时，这些突变的胰酶分子都不会引起胰腺炎或任何明显的扰动。然而，当R122G或Trypon小鼠被喂以酒精饮食时，它们会产生严重的CP。这些数据支持一种假设，即酒精使胰腺对影响胰酶激活或保护活性的胰酶的因素敏感。这项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。目的#1：确定急性或慢性酒精摄入对于表达突变胰酶的小鼠产生CP是必要的。酒精有多种影响，而急性酒精和慢性酒精的影响往往相反。在这个模型中，了解酒精是在短期还是长期内导致慢性胰腺炎是很重要的。我们还将确定酒精对胰酶活性的影响，以评估胰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。目的#2：我们将确定乙醇引起这些动物的腺泡细胞死亡的形式(S)。我们假设酒精扰乱了正常的细胞机制，细胞内的胰酶导致腺泡细胞的坏死。在这个模型中，我们还将检查自噬是否与乙醇的作用有关。目的#3.确定金属硫蛋白(MT)在酒精处理表达突变胰酶的小鼠慢性胰腺炎发生中的作用。我们先前已经发现，酒精喂养会导致MT下调，而MT通常在急性胰腺炎中起到保护作用。为了了解MT在酒精相关CP中的作用，我们将研究MT高水平(锌处理)或低水平(MT缺乏)小鼠突变胰酶表达的影响。我们还将探讨酒精减少MT表达的机制。总之，这些新的模型和方法将为酒精和胰腺疾病之间的关系提供重要的新信息。