Role of Intra-Pancreatic Trypsinogen Activation in Alcoholic Pancreatitis

胰腺内胰蛋白酶原激活在酒精性胰腺炎中的作用

• 批准号: 8384693
• 负责人: Rajinder K Dawra
• 金额: $ 21.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384693
• 关键词: Acinar Cell; Acute; Alcohol abuse; Alcoholic Pancreatitis; Alcohols; Applications Grants; Cathepsins B; Chronic; Development; Disease; Enzymes; Ethanol; Evaluation; Event; Experimental Animal Model; Experimental Models; Fibrosis; Foundations; Frequencies; Future; Gene Deletion; Genetic; Hospitalization; Human; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injury; Investigation; Knock-out; Knockout Mice; Lead; Mediating; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Pancreas; Pancreatic Injury; Pancreatitis; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Positioning Attribute; Predisposing Factor; Publications; Role; Staging; Stress; Testing; Trypsin; Trypsinogen; acute pancreatitis; alcohol exposure; biological adaptation to stress; cell injury; endoplasmic reticulum stress; feeding; in vitro Model; in vivo Model; mitochondrial autophagy; mortality; new therapeutic target; non-alcoholic; pancreatic juice; premature; problem drinker; response to injury; stem; therapeutic target; tool

DESCRIPTION (provided by applicant): Role of intra-pancreatic trypsinogen activation in alcoholic pancreatitis ABSTRACT Pancreatitis is an inflammatory disease of the pancreas associated with significant morbidity and mortality and is most commonly associated with alcohol abuse. However, the mechanism of alcoholic pancreatitis is not clear. It is believed that alcohol sensitizes the pancreas to genetic or environmental predisposing factors. A challenge remains to identify sensitization factors, to define their contribution to the injury and to understand the mechanisms of ethanol sensitizing effects. There is therefore an inarguable need to better understand the patho-physiological mechanism of alcoholic pancreatitis to develop a targeted therapy for the disease. Existing studies in non-alcoholic models of pancreatitis suggest a role for trypsinogen activation within the pancreas in the pathogenesis of the disease. Alcohol exposure is known to enhance activation of trypsinogen in acinar cells. Pancreatic juice of human alcoholics was found to have increased levels of trypsinogens. These changes are thought to make acinar cells more prone to injury. These findings suggest that trypsinogen activation in the pancreas might be the central event in the pathogenesis of alcoholic pancreatitis, although there is no direct experimental evidence to prove this. Ethanol exposure has several other deleterious effects like altered NFkB activation and perturbed endoplasmic reticulum stress response, which have the potential to cause pancreatic damage. Recently, we have developed knockout mice lacking trypsinogen 7, the mouse cationic trypsinogen. These mice do not show pathological activation of trypsinogen. Cathepsin B activity is required for intra-acinar activation of trypsinogen and the mice with cathepsin B gene deletion also lack pathological trypsinogen activation. Our access to these two strains of mice places us in a unique position to define the role of trypsinogen activation in the pathogenesis of alcoholic pancreatitis. In the absence of trypsinogen activation, we will also be able to understand if other ethanol exposure-induced deleterious events have any role in pathogenesis of the disease. In this grant proposal, we will be testing the hypothesis that intra-acinar activation of trypsinogen is the critical early event in alcoholic pancreatitis leading to acinar cll injury and activation of inflammatory pathways which result in acute pancreatitis and when prolonged, these events leads to fibrosis and chronic inflammatory response of alcoholic pancreatitis. Completion of these studies, while clearly defining the role of trypsinogen activatio in alcohol abuse induced sensitization, will lay the foundation for future investigations focused on understanding the role of other ethanol induced events in the pancreas and the searching for potential therapeutic targets in alcoholic pancreatitis. PUBLIC HEALTH RELEVANCE: Alcohol abuse is the common factor associated with pancreatitis but the mechanism of alcoholic pancreatitis is not clear. There is inarguable need to understand key events in the pathogenesis of the disease in order to identify novel therapeutic targets. Alcohol exposure is believed to enhance trypsinogen activation in acinar cells making pancreas susceptible to injury. However, the role of active trypsin in alcoholic pancreatitis is no clear. This project application aims at understanding the role of intra-pancreatic activation of trypsinogen in pancreatic acinar cell injury and inflammatory response using newly generated mice with trypsinogen 7 gene deletion and mice with cathepsin B deletion, both of which do not demonstrate pathologic trypsin activation.

描述(申请人提供)：胰腺内胰酶原激活在酒精性胰腺炎中的作用摘要胰腺炎是一种胰腺炎症性疾病，与显著的发病率和死亡率有关，最常见的与酒精滥用有关。然而，酒精性胰腺炎的发病机制尚不清楚。据信，酒精会使胰腺对遗传或环境诱因敏感。一个挑战仍然是确定致敏因素，确定它们对损伤的贡献，并了解乙醇致敏效应的机制。因此，毫无疑问，有必要更好地了解酒精性胰腺炎的病理生理机制，以开发针对该疾病的靶向治疗。现有的关于非酒精性胰腺炎模型的研究表明，胰腺内的胰酶原激活在该疾病的发病机制中发挥了作用。众所周知，酒精暴露会增强腺泡细胞中胰蛋白酶原的激活。研究发现，人类酗酒者的胰液中胰酶原含量增加。这些变化被认为使腺泡细胞更容易受到损伤。这些发现表明，胰腺中的胰酶原激活可能是酒精性胰腺炎发病机制中的中心事件，尽管没有直接的实验证据来证明这一点。酒精暴露还有其他几种有害影响，如改变NFkB激活和扰乱内质网应激反应，这些都有可能导致胰腺损伤。最近，我们培育了缺乏胰酶原7的基因敲除小鼠，这是一种阳离子胰蛋白酶原。这些小鼠没有表现出胰蛋白酶原的病理性激活。组织蛋白酶B的活性是胰蛋白酶原在腺泡内激活所必需的，组织蛋白酶B基因缺失的小鼠也缺乏病理性的胰蛋白酶原激活。我们接触到这两个品系的小鼠，使我们处于一个独特的位置，以确定胰酶原激活在酒精性胰腺炎发病机制中的作用。在没有胰酶原激活的情况下，我们也将能够了解酒精暴露引起的其他有害事件是否在疾病的发病机制中起到任何作用。在这项拨款提案中，我们将检验这一假说，即胰酶原在腺泡内的激活是酒精性胰腺炎的关键早期事件，导致腺泡CLL损伤和炎症通路的激活，从而导致急性胰腺炎，当持续时间延长时，这些事件会导致酒精性胰腺炎的纤维化和慢性炎症反应。这些研究的完成，虽然明确了胰酶原激活在酒精滥用诱导的敏化中的作用，但将为未来的研究奠定基础，重点是了解其他乙醇诱导的事件在胰腺中的作用，并寻找酒精性胰腺炎的潜在治疗靶点。 公共卫生相关性：酗酒是与胰腺炎相关的常见因素，但酒精性胰腺炎的发病机制尚不清楚。为了确定新的治疗靶点，了解疾病发病机制中的关键事件是毋庸置疑的需要。酒精暴露被认为增强了腺泡细胞中胰蛋白酶原的激活，使胰腺更容易受到损伤。然而，活性胰酶在酒精性胰腺炎中的作用尚不清楚。本项目旨在利用新生的胰蛋白酶原7基因缺失的小鼠和组织酶B缺失的小鼠，了解胰蛋白酶原在胰腺内激活在胰腺腺泡细胞损伤和炎症反应中的作用。