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

项目总结 衰老与生理功能障碍和患慢性病的风险增加有关。一个主要的 随着年龄的增长，调节生理功能障碍的机制，也是衰老的标志之一，是 慢性低度炎症，称为“炎症老化”。因此，正如在NIA PAR-15-190中强调的那样， 寻找新的抗炎疗法来减少炎症老化是治疗的首要任务 预防和治疗随年龄增长的生理功能障碍。 最近，合作研究员查尔斯·迪纳雷洛博士-翻译细胞因子生物学和 药物表征了一种新的内源性抗炎蛋白，白介素37(IL-37)。IL-37 通过强烈抑制炎症和不良免疫反应来减少发病率的发展 广泛的疾病模型。我们的初步数据表明，IL-37对血管有有益的作用， 新陈代谢和身体/运动功能随年龄增长。我们建议将我们的初步研究扩展到小鼠和 将我们的发现转化为中老年(MA/O)人类。具体地说，我们假设： (1)IL-37通过减少促炎信号，导致血管增强，从而抑制炎症老化。 小鼠的代谢和身体/运动功能随着年龄的增长而变化。为了检验这一假设，我们将确定 终身表达人IL-37的转基因小鼠和重组IL-37治疗的野生型小鼠 在晚年，表现出血管(内皮功能、主动脉僵硬)、代谢(胰岛素/葡萄糖)增强 功能)和体能/运动(运动能力、握力、耐力)相比较 各对照组(即转基因：老年野生型小鼠；重组IL-37：赋形剂处理对照组)。 (2)血浆IL-37浓度(正)和基因变异(负或正)将与 年轻和MA/O健康人的血管、代谢和身体/运动功能。我们将联系到流传 IL-37水平和IL-37基因中的单核苷酸多态性(SNPs)与相同的血管，代谢， (1)中描述的身体/运动功能，但在健康的年轻人和MA/O人群中。IL-37将在 储存的血浆样本来自实验室数据库，其中&gt；300名受试者已经进行了表型鉴定。 这项拟议的研究将是此类研究中第一次调查内源性抗-HBs的影响。 炎症介质IL-37对增龄大鼠多个临床相关生理功能的影响 无论是老鼠还是人类。这些研究的结果将为这两种机制的作用提供初步证据 以及IL-37随着人类衰老而维持/增强功能的治疗潜力。

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.