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: 8546290
• 负责人: Rajinder K Dawra
• 金额: $ 16.79万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546290
• 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.

描述（由申请人提供）：胰腺内胰蛋白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性疾病，与显著的发病率和死亡率相关，并且最常见与酒精滥用相关。然而，酒精性胰腺炎的发病机制尚不清楚。据信，酒精使胰腺对遗传或环境诱发因素敏感。一个挑战仍然是确定致敏因素，以确定其对损伤的贡献，并了解乙醇致敏作用的机制。因此，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。在非酒精性胰腺炎模型中的现有研究表明胰腺内胰蛋白酶原激活在疾病发病机制中的作用。已知酒精暴露可增强腺泡细胞中胰蛋白酶原的活化。研究发现，酗酒者的胰液中胰蛋白酶原的含量增加。这些变化被认为使腺泡细胞更容易受伤。这些结果表明，胰蛋白酶原激活的胰腺可能是在酒精性胰腺炎的发病机制的中心事件，虽然没有直接的实验证据来证明这一点。乙醇暴露具有几种其他有害作用，如改变的NF κ B活化和扰动的内质网应激反应，其具有引起胰腺损伤的潜力。最近，我们已经开发出敲除小鼠缺乏胰蛋白酶原7，小鼠阳离子胰蛋白酶原。这些小鼠未显示胰蛋白酶原的病理活化。腺泡内胰蛋白酶原活化需要组织蛋白酶B活性，并且具有组织蛋白酶B基因缺失的小鼠也缺乏病理性胰蛋白酶原活化。我们对这两种小鼠的研究使我们处于一个独特的位置，以确定胰蛋白酶原激活在酒精性胰腺炎发病机制中的作用。在缺乏胰蛋白酶原激活的情况下，我们也将能够了解其他乙醇缺乏诱导的有害事件是否在疾病的发病机制中起任何作用。在这项资助计划中，我们将检验以下假设：腺泡内胰蛋白酶原激活是酒精性胰腺炎的关键早期事件，导致腺泡细胞损伤和炎症通路激活，从而导致急性胰腺炎，当时间延长时，这些事件导致纤维化和酒精性胰腺炎的慢性炎症反应。这些研究的完成，明确了胰蛋白酶原激活在酒精滥用诱导的致敏中的作用，将为未来的研究奠定基础，重点是了解其他酒精诱导的胰腺事件的作用，并寻找酒精性胰腺炎的潜在治疗靶点。