Translational Studies of Interleukin-37, a Novel Anti-inflammatory Cytokine, for Prevention and Treatment of Inflamm-aging and Age-Associated Physiological Dysfunction

Interleukin-37（一种新型抗炎细胞因子）用于预防和治疗炎症衰老和年龄相关生理功能障碍的转化研究

• 批准号: 9172977
• 负责人: DOUGLAS R SEALS
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172977
• 关键词: 5' -AMP-activated protein kinase; Acute; Adherence; Adult; Adverse effects; Aerobic Exercise; Age; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Behavior; Biology; Blood Vessels; Chronic; Chronic Disease; Control Groups; Coupled; Data; Databases; Development; Disease; Disease model; Elderly; Exhibits; Functional disorder; Genes; Glucose; Hand Strength; High Fat Diet; Human; Immune response; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Interleukin-1; Interleukins; International; Laboratories; Life Style; Link; Measurement; Measures; Mediating; Medicine; Metabolic; Morbidity - disease rate; Motor; Mus; Mutation; Outcome; Patients; Phenotype; Physical Function; Physical Performance; Physiological; Plasma; Prevention; Preventive Intervention; Process; Proteins; Recombinant Interleukins; Recombinants; Research; Research Personnel; Rheumatoid Arthritis; Risk; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Testing; Therapeutic; Thick; Time; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Translational Research; United States National Institutes of Health; Wild Type Mouse; Work; age related; aged; clinically relevant; cohort; cost; cytokine; exercise capacity; feeding; functional decline; functional outcomes; gain of function mutation; genetic variant; healthy aging; healthy lifestyle; improved; inflammatory marker; insight; insulin signaling; middle age; motor disorder; mouse model; novel; prevent; response; translational study

PROJECT SUMMARY Aging is associated with physiological dysfunction and increased risk for developing chronic disease. A primary mechanism mediating physiological dysfunction with advancing age, and one of the hallmarks of aging, is chronic low-grade inflammation, termed “inflamm-aging”. Thus, as emphasized in NIA PAR-15-190, identifying novel anti-inflammatory therapies that reduce inflamm-aging is a high priority for preventing and treating physiological dysfunction with aging. Recently, co-investigator Dr. Charles Dinarello – an international leader in translational cytokine biology and medicine – characterized a novel endogenous anti-inflammatory protein, interleukin-37 (IL-37). IL-37 reduces development of morbidity by strongly suppressing inflammation and adverse immune responses in a wide spectrum of disease models. Our preliminary data suggest that IL-37 has beneficial effects on vascular, metabolic, and physical/motor function with aging. We propose to extend our initial studies in mice and translate our findings to middle-aged/older (MA/O) humans. Specifically, we hypothesize that: (1) IL-37 will suppress inflamm-aging by reducing pro-inflammatory signaling, resulting in enhanced vascular, metabolic and physical/motor function with aging in mice. To test this hypothesis, we will determine if transgenic mice with lifelong human IL-37 expression, as well as wild-type mice treated with recombinant IL-37 in late life, demonstrate enhanced vascular (endothelial function, aortic stiffness), metabolic (insulin/glucose function) and physical/motor (exercise capacity, grip strength, endurance) function compared to their respective control groups (i.e., transgenic: old wild-type mice; recombinant IL-37: vehicle-treated controls). (2) Plasma IL-37 concentrations (positively) and gene variants (negatively or positively) will be related to vascular, metabolic and physical/motor function in young and MA/O healthy humans. We will relate circulating IL-37 levels and single nucleotide polymorphisms (SNPs) in the IL-37 gene to the same vascular, metabolic, physical/motor functions described in (1), but in healthy young and MA/O humans. IL-37 will be measured in stored plasma samples from a laboratory database in which >300 subjects have already been phenotyped. The proposed research will be the first of its kind to investigate the effects of the endogenous anti- inflammatory mediator IL-37 on multiple domains of clinically relevant physiological function with aging in both mice and humans. The results of these studies will provide initial evidence for both the mechanistic role and therapeutic potential of IL-37 to maintain/enhance function with human aging.

项目摘要 衰老与身体功能障碍和患上慢性疾病的风险增加有关。主要 介导身体功能障碍随着年龄的增长和衰老的标志之一的机制是 慢性低度炎症称为“炎症”。正如NIA在15-190的NIA强调的那样， 确定减少炎症衰老的新型抗炎疗法是高度优先级 防止和治疗衰老的身体功能障碍。 最近，共同研究员查尔斯·迪纳雷洛（Charles Dinarello）博士 - 转化细胞因子生物学的国际领导者 药物 - 特征是一种新型的内源性抗炎蛋白，白介素37（IL-37）。 通过强烈抑制注射和不良免疫反应来降低发病率的发展 广泛的疾病模型。我们的初步数据表明，IL-37对血管有益影响， 代谢和衰老的物理/运动功能。我们建议在小鼠和 将我们的发现转化为中年/年龄较大的（ma/o）人类。具体来说，我们假设： （1）IL-37将通过减少促炎信号传导来抑制炎症，从而增强血管， 老鼠的代谢和物理/运动功能具有衰老。为了检验这一假设，我们将确定是否 具有终身IL-37表达的转基因小鼠，以及用重组IL-37处理的野生型小鼠 在后期，表现出增强的血管（内皮功能，主动脉僵硬），代谢（胰岛素/葡萄糖） 功能）和物理/运动（锻炼能力，抓地力，耐力）功能 各自的对照组（即转基因：旧野生型小鼠；重组IL-37：媒介物处理的对照）。 （2）等离子体IL-37浓度（积极地）和基因变异（负或积极）与 年轻人和MA/O健康人的血管，代谢和身体/运动功能。我们将关联流通 IL-37水平和IL-37基因中同一血管，代谢的IL-37基因中的单核苷酸多态性（SNP） （1）中描述的物理/运动功能，但在健康的年轻人和Ma/o人类中。 IL-37将在 从实验室数据库中存储的血浆样品，其中已经表现出> 300名受试者。 拟议的研究将是研究内源性抗 - 的影响的第一个 炎症介质IL-37在临床相关生理功能的多个领域，衰老 老鼠和人类。这些研究的结果将为机械作用提供初步证据 IL-37的治疗潜力以及通过人类衰老来维持/增强功能。