A model of obesity-associated severe acute pancreatitis

肥胖相关重症急性胰腺炎模型

• 批准号: 7229964
• 负责人: Giamila Fantuzzi
• 金额: $ 15.05万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229964
• 关键词: Acute-Phase Proteins; Apoptosis; Attention; Blood Circulation; Caerulein; Cells; Daily; Data; Development; Diet; Disease; Dose; Experimental Models; Future; Goals; Hepatic; Histology; Human; Immune; Immune Cell Activation; Interleukin-12; Interleukin-18; Kinetics; Leptin; Link; Measures; Mediator of activation protein; Metabolic; Modeling; Mus; Non obese; Obese Mice; Obesity; Pancreas; Pancreatitis; Pathology; Pathway interactions; Patients; Personal Satisfaction; Play; Population; Preventive; Pulmonary Pathology; Purpose; Rate; Research Personnel; Risk Factors; Schedule; Severities; System; Therapeutic; Wild Type Mouse; acute pancreatitis; cell type; cytokine; day; lung development; novel; programs; pulmonary function; research study; response; tool

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）：肥胖是发展为严重急性胰腺炎（AP）的一个明显的危险因素。然而，肥胖增加AP严重程度的机制目前尚不清楚。本研究旨在建立一种与肥胖相关的严重AP的新型实验模型。初步数据表明，在非肥胖野生型小鼠中，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）3至5天，可引起轻度胰腺损伤，但在瘦素缺乏、严重肥胖的ob/ob小鼠中，可引起非常严重的AP。本项目的目标是对这种肥胖相关的严重AP的新模型进行详细的表征，并希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、免疫细胞激活和代谢参数来研究哪些介质参与了该模型。耗竭和中和实验将试图确定在该模型中导致胰腺病理的细胞群和细胞因子。该新模型还将与已建立的小颗粒蛋白诱导AP模型进行比较。本探索性项目将验证是否一种新的、病理相关的重度AP模型可以作为研究肥胖相关重度AP的机制和可能的预防/治疗策略的合适工具。