Acute pancreatitis and obesity

急性胰腺炎与肥胖

基本信息

批准号：
8096750
负责人：
Giamila Fantuzzi
金额：
$ 32.19万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2010-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8096750
关键词：
2,4-thiazolidinedione Acinar Cell Acute Acute-Phase Proteins Acute-Phase Reaction Adipose tissue Animals Anti-Inflammatory Agents Anti-inflammatory Cell Line Cells Chronic Clinical Complex Development Disease Disease model Drug usage Exhibits Experimental Models Family Fatty Liver Functional disorder Future Goals Hepatic Human IRF1 gene In Vitro Individual Inflammation Inflammatory Inflammatory Response Insulin Resistance Interleukin-12 Interleukin-18 Interleukin-6 Knockout Mice Lead Life Link Mediating Metabolic Metabolic syndrome Metformin Modeling Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pancreas Pathway interactions Patients Pharmaceutical Preparations Phase Production Proteins Resolution Risk Factors Role Secondary to Severities Severity of illness Signal Pathway Signal Transduction Taurocholate Sodium Testing Thiazolidinediones Tissues Translating Up-Regulation Wound Healing acute pancreatitis cytokine design effective therapy glucose metabolism improved in vivo interleukin-22 lipid metabolism novel prevent public health relevance research study response restoration trait

项目摘要

DESCRIPTION (provided by applicant): Acute pancreatitis (AP) can range from a mild self-limited condition to a very severe life-threatening disease. Obesity is a risk factor for development of severe AP. No effective therapies for AP exist, partly as a result of lack of pathologically relevant models for this disease. We developed a novel, pathologically relevant model of AP induced in mice by co-administration of IL-12 and IL-18, two cytokines that participate in the inflammatory response in AP. In this model, obesity highly increases AP severity. The overall aim of this proposal is to identify mechanisms leading to resolution of AP in lean mice and - in contrast - to enhanced disease severity in obese animals, with the ultimate goal of translating these results to the clinical setting. The model of IL-1218- induced AP will be used and results confirmed using the cerulein and sodium taurocholate models. A mild increase in IL-6 and IL-22 levels is observed in lean mice injected with IL-1218, whereas obese mice exhibit a heightened response. In Aim 1, knock-out mice, neutralization experiments and administration of exogenous cytokines will be employed to test the hypotheses that: a) moderate levels of IL-6 and IL-22 mediate the anti-inflammatory and tissue repair responses that lead to efficient resolution of AP in lean animals; b) excessive production of IL-6 and IL-22 in obese mice leads to development of an exacerbated hepatic acute-phase response, with loss of anti- inflammatory and tissue-repair effects in the pancreas. The family of Regenerating (Reg) proteins is highly induced in the damaged pancreas and contributes to tissue repair. Induction of Reg proteins is significantly blunted in the pancreas of obese mice receiving IL-1218. In aim 2, we will test the hypothesis that pancreatic tissue in obese mice is unresponsive to factors that upregulate Reg proteins. Insulin resistance and fatty liver are common traits in obesity. In aim 3, we will test the hypothesis that obesity-associated metabolic dysfunction contributes to increased AP severity in obese mice. The effect of metformin or thiazolidinediones- two drugs commonly used in insulin-resistant patients - on AP severity as well as production of cytokines and acute-phase proteins in lean and obese will be evaluated, together with degree of hepatic steatosis and markers of lipid and glucose metabolism. PUBLIC HEALTH RELEVANCE: This proposal aims at increasing our understanding of the mechanisms linking obesity to increased severity of acute pancratitis, an inflammatory disease of the pancreas for which we do not know the cause and we do not currently have any effective treatments. Although the proposed studies are not aimed at directly generating new therapies for this inflammatory disease, a better understanding of the complex mechanisms involved will be useful for future novel treatments and - ideally - also to design possible strategies to prevent disease.

描述（由申请人提供）：急性胰腺炎（AP）的范围可以从轻微的自限性疾病到非常严重的危及生命的疾病。肥胖是发生严重 AP 的危险因素。 AP 尚无有效的治疗方法，部分原因是缺乏该疾病的病理相关模型。我们开发了一种新的、病理相关的 AP 模型，通过共同施用 IL-12 和 IL-18（两种参与 AP 炎症反应的细胞因子）在小鼠中诱导。在该模型中，肥胖会显着增加 AP 的严重程度。该提案的总体目标是确定导致瘦小鼠 AP 消退的机制，相反，肥胖动物中疾病严重程度增加的机制，最终目标是将这些结果转化为临床环境。将使用IL-1218诱导的AP模型，并使用雨蛙素和牛磺胆酸钠模型确认结果。在注射 IL-1218 的瘦小鼠中观察到 IL-6 和 IL-22 水平轻度增加，而肥胖小鼠则表现出更高的反应。在目标 1 中，将采用基因敲除小鼠、中和实验和外源细胞因子的施用来测试以下假设：a) 中等水平的 IL-6 和 IL-22 介导抗炎和组织修复反应，从而产生有效的瘦动物中 AP 的分辨率； b) 肥胖小鼠中IL-6和IL-22的过量产生导致肝脏急性期反应加剧，并导致胰腺失去抗炎和组织修复作用。再生 (Reg) 蛋白家族在受损的胰腺中被高度诱导，有助于组织修复。在接受 IL-1218 的肥胖小鼠的胰腺中，Reg 蛋白的诱导显着减弱。在目标 2 中，我们将检验肥胖小鼠的胰腺组织对上调 Reg 蛋白的因子没有反应的假设。胰岛素抵抗和脂肪肝是肥胖症的常见特征。在目标 3 中，我们将检验肥胖相关代谢功能障碍导致肥胖小鼠 AP 严重程度增加的假设。将评估二甲双胍或噻唑烷二酮类（胰岛素抵抗患者常用的两种药物）对 AP 严重程度以及瘦和肥胖者细胞因子和急性期蛋白产生的影响，以及肝脂肪变性程度和脂质和脂质标志物。葡萄糖代谢。公共健康相关性：该提案旨在加深我们对肥胖与急性胰腺炎严重程度增加之间联系的机制的了解，急性胰腺炎是一种胰腺炎症性疾病，我们不知道其原因，目前也没有任何有效的治疗方法。尽管拟议的研究并非旨在直接针对这种炎症性疾病产生新疗法，但更好地了解所涉及的复杂机制将有助于未来的新疗法，并且理想情况下还有助于设计预防疾病的可能策略。