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.

项目概要： 痛风是一种由尿酸盐晶体介导的激活引起的衰弱性炎症性疾病 高脂肪饮食诱导的 NLRP3 炎症体的衰老和代谢综合征。 Nalp3/NLRP3（NOD、LRR 和pyrin）的激活是痛风的主要危险因素。 域包含）通过尿酸盐晶体诱导募集和自催化处理 半胱氨酸蛋白酶 caspase-1 在称为“炎症小体”的大型胞质蛋白复合物中。 caspase-1 的激活是裂解储存的 IL-1β 前体和 IL-18 蛋白转化为具有生物活性的分泌细胞因子。 需要 ASC 的热蛋白结构域 (PYD) 的相互作用（对于凋亡相关斑点样 含有羧基末端的蛋白质 CARD) 与 Nlrp3 的 PYD 形成功能性 通过 CARD-CARD（半胱天冬酶激活招募结构域）形成炎性体复合物 ASC 与 procaspase-1 酶原的相互作用因此是内源性途径。 使炎症小体失活的代谢物具有很高的临床影响。 该提案基于我们最近的发现，即酮代谢物 β-羟基丁酸 (BHB) 阻断 NLRP3 炎性体以调节先天免疫反应。 BHB 和乙酰乙酸 (AcAc) 是替代代谢燃料，支持 作为 TCA 中 ATP 的来源，哺乳动物在饥饿期间得以生存 基于我们最初的发现和强有力的科学依据。 前提1，本项目的中心假设是生酮底物转换 调节性骨髓反应的基础，通过抑制代谢炎症 推论是，升高 BHB 可能是一种作用。 使用调节酮的饮食和转基因方法治疗痛风。 身体新陈代谢，这个提案将测试BHB如何控制新陈代谢的机制 巨噬细胞和中性粒细胞中炎症小体的激活是该研究的长期目标。 该项目是开发酮代谢物作为痛风疗法。