Impact of Ketone Metabolites on Inflammasome Deactivation in Gout

酮代谢物对痛风炎症小体失活的影响

• 批准号: 9216426
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216426
• 关键词: Ablation; Acetoacetates; Acute; Adipose tissue; Aging; Apoptosis; CASP1 gene; Carbon; Caspase; Cells; Citric Acid Cycle; Clinical; Coenzyme A; Complex; Crystal Formation; Crystallization; Data; Detection; Development; Diet; Disease; Enzyme Precursors; Enzymes; Fasting; Fever; Flare; Generations; Glucose; Glycolysis Inhibition; Goals; Gout; Gouty Arthritis; High Fat Diet; Human; Immune; Immune system; In Vitro; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1 beta; Interleukin-18; Joints; Ketone Bodies; Ketones; Label; Lipids; Liver; LoxP-flanked allele; Lyase; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolic syndrome; Metabolism; Methods; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Nonesterified Fatty Acids; Pain; Pathology; Pathway interactions; Patients; Production; Proteins; Protons; Rattus; Recruitment Activity; Regulation; Resolution; Risk Factors; Role; S100A8 gene; Signal Transduction; Source; Starvation; Testing; Therapeutic; Tissues; Transgenic Organisms; Urate; Work; base; beta-Hydroxybutyrate; cell type; cytokine; granulocyte; immunoregulation; in vivo; joint destruction; ketogenesis; ketogenic diet; ketogentic; macrophage; marenostrin; monocyte; neutrophil; novel; protein complex; response

PROJECT SUMMARY: Gout is a debilitating inflammatory disease caused by urate crystal mediated activation of the NLRP3 inflammasome. Aging and metabolic syndrome induced by high-fat diets are major risk factors for Gout. The activation of Nalp3/NLRP3 (for NOD, LRR and pyrin domain containing) by urate crystals induces recruitment and autocatalytic processing of cysteine protease caspase-1 in a large cytosolic protein complex called `inflammasome'. The activation of caspase-1, is required for the cleavage of stored pro-forms of IL-1β and IL-18 proteins into bioactive secreted cytokines. The assembly of inflammasomes requires interaction of pyrin domain (PYD) of ASC (for apoptosis-associated speck like protein containing carboxy terminal CARD) with PYD of Nlrp3 forming a functional inflammasome complex through CARD-CARD (caspase activation recruitment domain ) interaction of ASC with procaspase-1 zymogen. Therefore, the endogenous pathways and metabolites that deactivate the inflammasome have high clinical impact. This proposal is based on our recent findings that ketone metabolite β-hydroxybutyrate (BHB) blocks the NLRP3 inflammasome to regulate the innate immune response. The ketone bodies, BHB and acetoacetate (AcAc) are alternate metabolic fuels that support mammalian survival during periods of starvation by serving as a source of ATP in TCA cycle when glucose reserves are low. Based on our original findings and strong scientific premise1, the central hypothesis of this project is that ketogenic substrate switch underlies the regulatory myeloid responses that dampen metabolic inflammation via inflammasome deactivation. The corollary is that elevating BHB may serve as a treatment for Gout. Using both dietary and transgenic approaches that regulate ketone body metabolism, this proposal will test the mechanism of how BHB controls the inflammasome activation in macrophages and neutrophils. The long-term goal of this project is to develop ketone metabolites as therapeutics against Gout.

项目摘要： 痛风是由尿酸盐介导的激活引起的一种令人衰弱的炎症性疾病 NLRP3炎性体。高脂饮食引起的衰老和代谢综合征 是痛风的主要风险因素。 NALP3/NLRP3的激活（用于点头，LRR和Pyrin 尿酸晶晶体包含域）诱导募集和自催化处理 大型胞质蛋白复合物中的半胱氨酸蛋白caspase-1称为“炎症体”。 caspase-1的激活是裂解IL-1β和 IL-18蛋白成生物活性分泌的细胞因子。炎症的组装 需要ASC的吡啶结构域（PYD）的相互作用（用于凋亡相关的斑点 含有NLRP3的PYD的蛋白质含有羧基终端卡）形成功能性的 通过卡片卡（caspase Actipation募集域）的炎性体复合体 ASC与procaspase-1 zymogen的相互作用。因此，内源性途径 释放炎症体的代谢产物具有很高的临床影响。这 建议基于我们最近的发现，酮代谢产物β-羟基丁酸（BHB） 阻止NLRP3炎症体调节先天免疫反应。酮 身体，BHB和乙酰乙酸（ACAC）是支持的替代代谢燃料 在饥饿期间，哺乳动物的生存是通过作为TCA中ATP来源的 葡萄糖储量低的循环。根据我们的原始发现和强大的科学 前提1，该项目的中心假设是生酮底物开关 是通过调节性髓样反应的基础 炎性体停用。推论是提高BHB可以用作 治疗痛风。使用调节酮的饮食和转基因方法 身体代谢，该提案将测试BHB如何控制的机制 巨噬细胞和中性粒细胞中的炎性体激活。这个长期目标 项目是开发酮代谢物作为对痛风的治疗。