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

香葱叶衍生的外泌体样纳米颗粒可降低肥胖症中的 NLRP3 炎症小体活性

• 批准号: 9795743
• 负责人: Jiujiu Yu
• 金额: $ 22.64万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9795743
• 关键词: Adipose tissue; Allium schoenoprasum; Animal Model; Animals; Anti-inflammatory; Area; Bioavailable; Biodistribution; Biological; Cardiovascular system; Cause of Death; Cell Culture Techniques; Chronic; Control Groups; Diabetes Mellitus; Diet; Disease; Dyes; Eating; Flowers; Food; Foundations; Future; Gene Expression; Genetic; Glucose; Goals; Health; Heart; Heart Diseases; High Fat Diet; Human; Incubated; Individual; Infiltration; Inflammasome; Inflammation; Inflammatory; Insulin; Interleukin-1; Intestines; Investigation; Label; Lipids; Liver; Mass Spectrum Analysis; Measures; Mediator of activation protein; Membrane; Membrane Lipids; Membrane Proteins; Metabolic; Modality; Modeling; Molecular; Mus; Nebraska; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Oral; Organ; Outcome; Output; Pathway interactions; Patients; Pattern; Phosphate Buffer; Pilot Projects; Plant Leaves; Plasma; Progressive Disease; Proteins; RNA; Research; Resources; Safety; Saline; Signal Pathway; Signal Transduction; Solvents; Spleen; Stroke; Testing; Therapeutic; Thermogenesis; Thinness; Tissues; Translations; United States; Vegetables; Vesicle; Work; cancer type; exosome; fasting plasma glucose; foodborne; glucose tolerance; improved; in vivo; inhibitor/antagonist; innovation; insulin sensitivity; macrophage; nanoparticle; novel therapeutics; obesity prevention; prevent; small molecule inhibitor; stem; uptake

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.

项目总结/摘要 肥胖是一种慢性进行性疾病，在美国导致几种主要死亡原因，包括 心脏病、中风、糖尿病和某些癌症。慢性炎症被认为是 促进肥胖相关疾病的发生和发展。NLRP 3炎性小体是 肥胖相关慢性炎症的介质。然而，没有有效和安全的策略， 开发用于抑制肥胖症中的NLRP 3炎性体和慢性炎症。因此，余博士的长期- 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 和肥胖相关的疾病。作为第一步，该项目将集中在韭菜叶衍生的外泌体样 纳米颗粒（CL-ELN），因为初步研究表明CL-ELN强烈抑制NLRP 3炎性小体 在巨噬细胞中激活，而来自其他九种蔬菜的ELN不抑制NLRP 3炎性小体 活动在这项初步工作的基础上，该项目将测试中心假设，即CL-ELN含有活性 抑制NLRP 3炎性体活性并改善肥胖症中代谢性炎症的生物分子。这 假设将通过两个特定目标（SA）进行测试：SA 1）识别CL-ELN中的活性生物分子， 抑制NLRP 3炎性体活性和SA 2）评价CL-ELN对代谢性炎症和 肥胖动物模型的代谢健康。为了达到SA 1，将检查CL-ELN中的生物分子， 确定对NLRP 3炎性体抑制至关重要的活性生物分子。“组学”分析将用于 通过比较CL-ELN的“组学”特征，鉴定CL-ELN中特异性富集的生物分子 与对NLRP 3炎性体没有抑制作用的其它饮食ELN相比。这些生物分子 将单独测试它们对炎性小体活性的影响。在SA 2中，C57 BL/6 J小鼠将被 喂食高脂肪饮食以诱导肥胖、NLRP 3炎性体活化和慢性炎症。老鼠成 口服CL-ELN（治疗组）或溶剂（对照组）。NLRP 3炎性小体，慢性 炎症状态和代谢健康将通过测量： 脂肪组织巨噬细胞;代谢组织中的巨噬细胞浸润和炎症基因表达; 空腹血糖和胰岛素水平;葡萄糖耐量;胰岛素敏感性;和血浆代谢物水平 和代谢组织中的代谢基因表达。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NLRP 3的新疗法的第一步 炎症小体和慢性炎症。这些成果与专题重点密切一致 内布拉斯加州通过膳食分子预防肥胖中心（NPOD）-识别生物 食源性信号，以预防，治疗和治愈肥胖和相关疾病-鉴于CL-ELN是这样一个 食物信号