Acute pancreatitis and obesity

急性胰腺炎与肥胖

• 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
• 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

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）的范围可以从轻度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没有有效的治疗方法，部分原因是缺乏这种疾病的病理相关模型。我们开发了一种新的，病理相关的AP模型诱导的小鼠共同管理的IL-12和IL-18，两种细胞因子参与AP的炎症反应。在这个模型中，肥胖大大增加了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，以及相反，导致肥胖动物疾病严重程度增强的机制，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，并使用雨蛙肽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水平的轻度增加，而肥胖小鼠表现出增强的反应。在目标1中，将采用基因敲除小鼠、中和实验和外源性细胞因子的施用来检验以下假设：a）中等水平的IL-6和IL-22介导抗炎和组织修复反应，导致瘦动物中AP的有效消退; B）肥胖小鼠中IL-6和IL-22的过量产生导致恶化的肝急性期反应的发展，胰腺中的抗炎和组织修复作用丧失。再生（Reg）蛋白家族在受损胰腺中高度诱导，并有助于组织修复。Reg蛋白的诱导在接受IL-1218的肥胖小鼠的胰腺中显著减弱。在目标2中，我们将检验肥胖小鼠的胰腺组织对上调Reg蛋白的因素无反应的假设。胰岛素抵抗和脂肪肝是肥胖的常见特征。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。将评价二甲双胍或噻唑烷二酮类（两种常用于胰岛素抵抗患者的药物）对AP严重程度以及瘦型和肥胖型患者细胞因子和急性时相蛋白产生的影响，以及肝脂肪变性程度和脂质和葡萄糖代谢标志物。 公共卫生关系：这项提案旨在增加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理解，急性胰腺炎是一种胰腺炎性疾病，我们不知道其原因，目前也没有任何有效的治疗方法。虽然拟议的研究不是为了直接产生这种炎性疾病的新疗法，但更好地了解所涉及的复杂机制将有助于未来的新治疗，理想情况下也可以设计预防疾病的可能策略。