Mechanism(s) of Alcoholic Pancreatitis

酒精性胰腺炎的发病机制

基本信息

批准号：
7983406
负责人：
BHUPENDRA S KAPHALIA
金额：
$ 22.95万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983406
关键词：
Acetaldehyde Acinar Cell Address Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcoholic Pancreatitis Alcohols Anatomy Animal Model Area Biliary Biological Markers Blood Blood alcohol level measurement Cell Death Chronic Chronic Disease Comorbidity Data Deer Mouse Development Diabetes Mellitus Disease Dose Duct (organ) structure Early Diagnosis Economics Endoplasmic Reticulum Enzyme Precursors Esters Ethanol Event Exocrine pancreas Fatty Acids Fatty Change Fibrosis Foundations Health Hepatic Homeostasis Infiltration Inflammatory Response Inflammatory Response Pathway Injury Intervention Investigation Lead Lipids Malignant neoplasm of pancreas Measures Metabolic Methods Modality Mouse Strains NMR Spectroscopy National Institute on Alcohol Abuse and Alcoholism Nature Nuclear Magnetic Resonance Oxidative Stress Pain Pancreas Pancreatic Injury Pancreatitis Pathway interactions Phosphorus Plasma Prevention Protons Qualifying Recovery of Function Reporting Research Research Personnel Research Project Grants Role Sclerosis Social Impacts Testing Therapeutic Therapeutic Intervention Tissues Translational Research acute pancreatitis alcohol exposure alcohol induced pancreatic injury base calcification chronic pancreatitis cytokine cytotoxic economic impact effective therapy endoplasmic reticulum stress experience feeding glucose-regulated proteins injured metabolomics morphometry mortality mouse model programs public health relevance response social transcription factor

项目摘要

DESCRIPTION (provided by applicant): Chronic pancreatitis is a serious and painful disorder of exocrine pancreas with no effective therapeutic measures. After biliary duct disease, chronic alcohol abuse is the second major cause of chronic pancreatitis. The economic and social impact of pancreatitis is devastating due to irreversible nature of the disease and related high mortality and co-morbidities including maldigestion, diabetes, and pancreatic cancer. Autodigestion of pancreatic tissue due to the activation of digestive zymogens in the exocrine pancreas is known to cause pancreatitis. However, metabolic basis of alcoholic pancreatitis is relatively obscure. Role of ethanol metabolites, acetaldehyde (oxidative metabolite) and fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites) in the initiation and progression of pancreatitis" is one of the focus areas of NIAAA sponsored research programs (PA-09-164). In preliminary dose-dependent studies, we found that pancreatic injury along with substantial increases in blood alcohol concentration (BAC) and pancreatic lipids, fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites of ethanol) and endoplasmic reticulum (ER) stress in hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) vs. normal ADH (ADH+) deer mice fed 3.5% ethanol (an optimal tolerable dose) for 2 months (subchronic exposure). However, the levels of blood acetaldehyde were found to be similar in both strains of deer mice fed ethanol. Based upon our preliminary data in deer mouse model and the cytotoxic effects of FAEEs reported by us and others in pancreatic acinar cells, we hypothesize that chronic ethanol exposure under hepatic ADH inhibition induces ER stress due to endogenous formation of nonoxidative lipid metabolites of ethanol in the exocrine pancreas resulting in initiation and progression of alcoholic pancreatitis. In Aim 1, we will characterize progression of lipid metabolomic changes and increases in FAEEs in the pancreas of ADH- deer mice after chronic ethanol exposure for 3 and 6 months. We will assess fatty changes and endogenous levels of FAEEs in the pancreas by proton and/or 31phosphorus nuclear magnetic resonance spectroscopy. In Aim 2, we will examine the progression of pancreatic injury, ER stress and proinflammatory responses in ethanol fed ADH- deer mice from Aim 1. Pancreatic injury will be evaluated by morphometry and injury markers, pancreatic ER stress by measuring the over expression of glucose regulated protein 78 and related cell death pathways, and inflammatory responses by proinflammatory transcription factors and cytokines in the pancreas and/or plasma. Our plasma data on markers of injury and changes in lipid metabolome can be utilized for early detection of developmental pancreatitis. The combined results of both aims should determine role/contribution of FAEEs in initiation and progression of alcoholic pancreatitis and identify its biomarkers. This information will be utilized to develop a translational research project for the early detection and intervention of alcoholic pancreatitis. Our strong existing interdisciplinary team of investigators and preliminary data in deer mouse model make us uniquely qualified to pursue this project. PUBLIC HEALTH RELEVANCE: NARRATIVE: Alcoholic pancreatitis is a devastating disease and painful disorder of exocrine pancreas often causes high mortality and associated with co-morbidities including maldigestion, diabetes, and pancreatic cancer. In this project, we will establish metabolic basis of alcoholic pancreatitis, and identify early markers of ethanol-induced pancreatic injury for a translational research project for early detection and prevention of alcoholic pancreatitis.

描述（由申请人提供）：慢性胰腺炎是一种严重而疼痛的外分泌胰腺疾病，没有有效的治疗方法。胆管疾病后，慢性酒精滥用是慢性胰腺炎的第二个主要原因。胰腺炎的经济和社会影响是由于该疾病的不可逆转性以及相关的高死亡率和合并症，包括马尔多斯，糖尿病和胰腺癌。由于外分泌胰腺中消化酶的激活而引起的胰腺组织自身消化，已知会引起胰腺炎。但是，酒精性胰腺炎的代谢基础相对晦涩。乙醇代谢产物，乙醛（氧化代谢产物）和脂肪酸乙基酯（FAEES，非氧化脂质代谢物）在胰腺炎的起始和进展中的作用。在血液酒精浓度（BAC）和胰腺脂质中，脂肪酸乙酯（FAEES，乙醇的非氧化脂质代谢产物）和内质网（ER）肝酒精（ER）胁迫（ER）抗性酒精脱氢酶（ADH）中缺乏（ADH-）的（ADH-）的ADH（ADH）（ADH）（ADH）（ADH）（ADH）（ADH+）deer（Adh+）deer+3.5％DEER MIMETER（ADH）中的脂肪（ER）胁迫（ER）胁迫。（亚基）。乙醇在外分泌胰腺中的非氧化脂质代谢产生，导致酒精性胰腺炎的启动和进展。在AIM 1中，我们将表征脂质代谢组变化的进展，并在慢性乙醇暴露3和6个月后ADH-DEHER小鼠胰腺中的FAEES增加。我们将通过质子和/或31磷核磁共振光谱法评估胰腺中FAEES的脂肪变化和内源水平。在目标2中，我们将检查胰损伤，ER压力和促炎性反应的进展。乙醇从AIM 1中进行的ADH-DEHER小鼠的进展。胰腺损伤将通过形态计量学和损伤标记来评估胰腺损伤，胰腺ER应激，通过通过葡萄糖调节的蛋白质78和相关的蛋白质死亡途径的过度表达来评估胰腺ER应激，并通过旋转蛋白78和相关的蛋白质反应来评估。胰腺和/或血浆。我们有关损伤标记和脂质代谢组变化的等离子体数据可用于早期发现发育性胰腺炎。这两个目标的综合结果应确定FAEE在酒精性胰腺炎的启动和进展中的作用/贡献，并确定其生物标志物。该信息将用于开发一个转化研究项目，用于早期检测和干预酒精性胰腺炎。我们在鹿鼠标模型中组成的研究人员和初步数据的现有强大的跨学科团队使我们拥有独特的资格来追求该项目。公共卫生相关性：叙事：酒精性胰腺炎是一种毁灭性的疾病和外分泌胰腺疼痛疾病，通常会导致高死亡率，并与包括Maldigestion，糖尿病和胰腺癌在内的合并症有关。在该项目中，我们将建立酒精性胰腺炎的代谢基础，并确定乙醇引起的胰腺损伤的早期标志物，以用于转化研究项目，以早期检测和预防酒精性胰腺炎。