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（申请人提供）：慢性胰腺炎是一种严重且痛苦的胰腺外分泌疾病，目前尚无有效的治疗措施。继胆管疾病之后，长期酗酒是慢性胰腺炎的第二大原因。由于胰腺炎的不可逆转性以及相关的高死亡率和消化不良、糖尿病和胰腺癌等合并症，胰腺炎的经济和社会影响是毁灭性的。已知由于外分泌胰腺中消化酶原的激活而导致的胰腺组织的自身消化会引起胰腺炎。然而，酒精性胰腺炎的代谢基础相对不清楚。乙醇代谢物、乙醛（氧化代谢物）和脂肪酸乙酯（FAEE，非氧化脂质代谢物）在胰腺炎的发生和进展中的作用”是 NIAAA 资助的研究项目 (PA-09-164) 的重点领域之一。初步的剂量依赖性研究，我们发现胰腺损伤伴随着血液酒精浓度（BAC）和胰腺脂质、脂肪酸乙酯（FAEEs、非氧化脂质）的大幅增加肝乙醇脱氢酶 (ADH) 缺陷 (ADH-) 与正常 ADH (ADH+) 鹿小鼠饲喂 3.5% 乙醇（最佳耐受剂量） 2 个月（亚慢性暴露）的乙醇代谢物）和内质网 (ER) 应激然而，根据我们在鹿小鼠模型和小鼠中的初步数据，发现喂食乙醇的两种鹿小鼠的血液乙醛水平相似。根据我们和其他人报道的 FAEE 对胰腺腺泡细胞的细胞毒性作用，我们假设在肝脏 ADH 抑制下长期接触乙醇会诱导 ER 应激，因为外分泌胰腺中乙醇的非氧化脂质代谢物内源性形成，导致酒精性胰腺炎的发生和进展。在目标 1 中，我们将描述长期乙醇暴露 3 个月和 6 个月后 ADH 鹿小鼠胰腺中脂质代谢组变化的进展和 FAEE 的增加。我们将通过质子和/或 31 磷核磁共振波谱评估胰腺中的脂肪变化和 FAEE 的内源水平。在目标 2 中，我们将检查目标 1 中乙醇喂养的 ADH-鹿小鼠的胰腺损伤、内质网应激和促炎反应的进展情况。将通过形态测定和损伤标记物评估胰腺损伤，通过测量葡萄糖的过度表达来评估胰腺内质网应激调节蛋白 78 和相关细胞死亡途径，以及胰腺和/或血浆中促炎转录因子和细胞因子的炎症反应。我们关于损伤标志物和脂质代谢组变化的血浆数据可用于早期检测发育性胰腺炎。这两个目标的综合结果应确定 FAEE 在酒精性胰腺炎发生和进展中的作用/贡献，并确定其生物标志物。这些信息将用于开发一个转化研究项目，以早期发现和干预酒精性胰腺炎。我们现有强大的跨学科研究团队和鹿鼠模型的初步数据使我们具有独特的资格来开展该项目。公共卫生相关性：叙述：酒精性胰腺炎是一种毁灭性的疾病，胰腺外分泌的痛苦性疾病常常导致高死亡率，并与消化不良、糖尿病和胰腺癌等合并症相关。在这个项目中，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，以开展早期检测和预防酒精性胰腺炎的转化研究项目。