Chive leaf-derived exosome-like nanoparticles decrease NLRP3 inflammasome activity in obesity

项目摘要/摘要 肥胖是一种慢性进行性疾病，在美国导致几个主要死亡原因，包括 心脏病、中风、糖尿病和某些类型的癌症。慢性炎症已被公认为 促进肥胖相关疾病的发生和发展。NLRP3炎症小体是关键之一 肥胖相关慢性炎症的中介物。然而，目前还没有有效和安全的战略。 开发用于抑制NLRP3炎症体和肥胖症的慢性炎症。因此，余博士的长- 长期目标是开发一种新的饮食策略或治疗方式来抑制肥胖症的慢性炎症 以及与肥胖相关的疾病。作为第一步，这个项目将专注于从香葱叶中提取的类似外显子的物质 纳米粒(CL-ELN)，因为一项初步研究表明CL-ELN强烈抑制NLRP3炎症小体 激活巨噬细胞，而其他9种蔬菜中的ELN不抑制NLRP3炎症体 活动。在这项前期工作的基础上，该项目将检验CL-ELN含有活性的中心假设 抑制NLRP3炎症体活性和改善肥胖代谢性炎症的生物分子。这 假设将通过两个特定的目的(SA)来检验：1)识别CL-ELN中的活性生物分子， 抑制NLRP3炎症体活性和SA2)评估CL-ELNS对代谢性炎症和 肥胖动物模型的代谢健康。为了实现SA1，将检测CL-ELN中的生物分子以 确定对抑制NLRP3炎症体至关重要的活性生物分子。“组学”分析将被用于 通过比较CL-ELN的组学特征，确定特定富含在CL-ELN中的生物分子 对于其他对NLRP3炎症小体没有抑制作用的饮食ELN。生物分子的富集化 在CL-ELN中，将单独测试它们对炎症体活动的影响。在SA2中，C57BL/6J小鼠将被 高脂饮食诱导肥胖、NLRP3炎症小体激活和慢性炎症。老鼠们会 口服CL-ELNS(治疗组)或溶剂(对照组)。NLRP3炎症体，慢性 炎症状态和代谢健康将通过测量：NLRP3炎症体活性来评估 脂肪组织巨噬细胞；代谢组织中巨噬细胞的浸润和炎症基因的表达； 空腹血糖和胰岛素水平；葡萄糖耐量；胰岛素敏感性；以及血浆代谢物水平 代谢组织中代谢基因的表达。成功完成拟议的研究将是 将CL-ELN中的活性生物分子转化为抑制NLRP3的新疗法的第一步 肥胖症的炎症性和慢性炎症。这些成果与主题重点密切相关。 内布拉斯加州通过饮食分子预防肥胖中心(NPOD)的研究--以鉴定生物学 预防、治疗和治愈肥胖及相关疾病的食源性信号--鉴于CL-ELN就是这样的一种 食物信号。

PROJECT SUMMARY/ABSTRACT Obesity is a chronic progressive disease that leads to several leading causes of death in United States, including heart disease, stroke, diabetes, and some types of cancer. Chronic inflammation has been recognized to promote the initiation and progression of obesity-related diseases. The NLRP3 inflammasome is one of the key mediators of obesity-related chronic inflammation. However, no effective and safe strategies have been developed to suppress the NLRP3 inflammasome and chronic inflammation in obesity. As such, Dr. Yu's long- term goal is to develop a new dietary strategy or therapeutic modality to suppress chronic inflammation in obesity and obesity-related diseases. As an initial step, this project will focus on chive leaf-derived exosome-like nanoparticles (CL-ELNs) because a pilot study suggested that CL-ELNs strongly inhibit NLRP3 inflammasome activation in macrophages, whereas the ELNs from nine other vegetables did not inhibit NLRP3 inflammasome activity. Building on this preliminary work, this project will test the central hypothesis that CL-ELNs contain active biomolecules that inhibit NLRP3 inflammasome activity and ameliorate metabolic inflammation in obesity. This hypothesis will be tested through two specific aims (SAs): SA1) identify the active biomolecules in CL-ELNs that inhibit NLRP3 inflammasome activity and SA2) evaluate effects of CL-ELNs on metabolic inflammation and metabolic health in obese animal models. To achieve SA1, the biomolecules in CL-ELNs will be examined to determine the active biomolecules critical to NLRP3 inflammasome inhibition. An `omics' analysis will be used to identify the biomolecules that are specifically enriched in CL-ELNs by comparing the `omics' profiles of CL-ELNs to other dietary ELNs that do not have inhibitory effects on the NLRP3 inflammasome. The biomolecules enriched in CL-ELNs will be tested individually for their effects on inflammasome activity. In SA2, C57BL/6J mice will be fed a high-fat diet to induce obesity, NLRP3 inflammasome activation, and chronic inflammation. The mice will be given orally CL-ELNs (treated group) or the solvent (control group). The NLRP3 inflammasome, chronic inflammation status, and metabolic health will be evaluated by measuring: NLRP3 inflammasome activity in adipose tissue macrophages; macrophage infiltration and inflammatory gene expression in metabolic tissues; fasting plasma glucose and insulin levels; glucose tolerance; insulin sensitivity; and plasma metabolite levels and metabolic gene expression in metabolic tissues. Successful completion of the proposed research will be the first step toward the translation of active biomolecules in CL-ELNs into novel therapies to suppress NLRP3 inflammasome and chronic inflammation in obesity. These outcomes are closely aligned with the thematic focus of the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD) – to identify biological food-borne signals to prevent, treat, and cure obesity and related diseases – given that CL-ELNs are one such food signal.