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（由申请人提供）：肥胖是严重急性胰腺炎（AP）发展的一个明确的危险因素。然而，肥胖增加 AP 严重程度的机制目前尚不清楚。该提案旨在开发一种与肥胖相关的严重 AP 的新型实验模型。初步数据表明，每日联合使用白细胞介素 12 和白细胞介素 18（AP 患者循环中增加的两种细胞因子）持续 3 至 5 天，可在非肥胖野生型小鼠中诱导轻度胰腺损伤，但会导致非常严重的 AP在瘦素缺乏、严重肥胖的 ob/ob 小鼠中。本项目的目标是对这种与肥胖相关的严重 AP 的新模型进行详细表征，并有望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、细胞凋亡率、免疫细胞活化和代谢参数来研究哪些介质参与该模型。耗竭和中和实验将尝试识别有助于该模型中胰腺病理学的细胞群和细胞因子。该新模型还将与已建立的由雨蛙素诱导的 AP 模型进行比较。该探索性项目将验证是否可以使用一种新型的、病理相关的严重AP模型作为合适的工具来研究肥胖相关的严重AP的机制和可能的预防/治疗策略。