A model of obesity-associated severe acute pancreatitis

肥胖相关重症急性胰腺炎模型

• 批准号: 7033425
• 负责人: Giamila Fantuzzi
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-08 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033425
• 关键词: acute disease /disorder; apoptosis; cytokine; disease /disorder model; disease /disorder proneness /risk; flow cytometry; immunoregulation; interleukin 12; laboratory mouse; leptin; model design /development; obesity; pancreatitis; pathologic process

DESCRIPTION (provided by applicant): Obesity is a well-characterized risk factor for development of severe acute pancreatitis (AP). However, the mechanisms by which obesity increases AP severity are currently unclear. This proposal aims at developing a novel experimental model of obesity-associated severe AP. Preliminary data indicate that daily administration of a combination of interleukin-12 and interleukin 18 - two cytokines that are increased in the circulation of AP patients - for 3 to 5 days induces mild pancreatic damage in non-obese wild type mice, but very severe AP in leptin-deficient, massively obese ob/ob mice. The goal of the present project is to perform a detailed characterization of this novel model of obesity-associated severe AP with the prospect of utilizing it in future studies to identify the mechanisms linking obesity to increased AP severity. We will evaluate the kinetics of disease and perform dose-response experiments. We will also study which mediators are involved in this model by measuring local and systemic cytokine levels and acute-phase proteins, rates of apoptosis, activation of immune cells, and metabolic parameters. Depletion and neutralization experiments will attempt to identify the cell populations and cytokines which contribute to pancreatic pathology in this model. The novel model will also be compared with the well-established model of AP induced by administration of caerulein. This exploratory project will verify whether a novel, pathologically relevant model of severe AP can be used as a suitable tool to investigate the mechanisms and possible preventive/therapeutic strategies of obesity-associated severe AP.

描述（由申请方提供）：肥胖是发生重症急性胰腺炎（AP）的一个特征明确的风险因素。然而，肥胖增加AP严重程度的机制目前尚不清楚。该建议旨在开发一种新的肥胖相关严重AP的实验模型。初步数据表明，每天给予白细胞介素-12和白细胞介素18 --两种在AP患者的循环中增加的细胞因子--的组合3至5天在非肥胖野生型小鼠中诱导轻度胰腺损伤，但在瘦素缺乏的严重肥胖ob/ob小鼠中诱导非常严重的AP。本项目的目标是对这种肥胖相关严重AP的新模型进行详细表征，并前景在未来的研究中利用它来确定肥胖与AP严重程度增加之间的联系机制。我们将评估疾病的动力学并进行剂量反应实验。我们还将通过测量局部和全身细胞因子水平和急性期蛋白、凋亡率、免疫细胞活化和代谢参数来研究该模型中涉及哪些介质。消耗和中和实验将试图鉴定在该模型中促成胰腺病理的细胞群和细胞因子。新的模型也将与雨蛙肽诱导的AP的良好建立的模型进行比较。该探索性项目将验证一种新的、病理相关的严重AP模型是否可以用作研究肥胖相关严重AP的机制和可能的预防/治疗策略的合适工具。