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Impact of Ketone Metabolites on Inflammasome Deactivation in Gout

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:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-03-01 至 2022-01-31

项目摘要

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中文摘要
翻译
项目概要: 痛风是一种由尿酸盐晶体介导的激活引起的使人衰弱的炎性疾病 NLRP 3炎性小体高脂饮食致衰老与代谢综合征 是痛风的主要危险因素。Nalp 3/NLRP 3的激活(对于NOD、LRR和pyrin 结构域包含)的尿酸盐晶体诱导招聘和自催化处理 半胱氨酸蛋白酶半胱天冬酶-1在称为“炎性体”的大胞质蛋白复合物中。 半胱天冬酶-1的活化是裂解储存的IL-1β前体和IL-10受体所必需的。 IL-18蛋白转化为生物活性分泌的细胞因子。炎性小体的组装 需要ASC的Pyrin结构域(PYD)的相互作用(对于细胞凋亡相关的斑点样 含有羧基末端CARD的蛋白质)与Nlrp 3的PYD形成功能性 通过CARD-CARD(半胱天冬酶激活募集结构域)的炎性小体复合物 ASC与半胱氨酸天冬氨酸蛋白酶原-1酶原相互作用。因此,内源途径 并且使炎性体失活的代谢物具有很高的临床影响。这 该建议是基于我们最近的发现,酮代谢物β-羟基丁酸酯(BHB) 阻断NLRP 3炎性体以调节先天性免疫应答。的酮 BHB和乙酰乙酸(AcAc)是替代代谢燃料, 哺乳动物在饥饿期间的生存,作为TCA中ATP的来源 当葡萄糖储备低时,循环。基于我们最初的发现和强大的科学 前提1,该项目的中心假设是生酮底物转换 是调节性髓样反应的基础, 炎性小体失活由此推论,提高BHB可能是一种 痛风的治疗使用饮食和转基因方法调节酮 身体代谢,这项建议将测试如何BHB控制的机制, 巨噬细胞和嗜中性粒细胞中的炎性小体活化。长期目标是 项目是开发酮代谢物作为治疗痛风的药物。
英文摘要
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.
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Caloric restriction-driven immunometabolic checkpoints of inflammation
  • 批准号:
    10457565
  • 项目类别:
  • 资助金额:
    $58.39万
  • 财政年份:
    2022
  • 负责人:
    VISHWA DEEP DIXIT
  • 依托单位:
Yale Murine-TMC on Immune Cell Senescence Derived Inflammation
  • 批准号:
    10675111
  • 项目类别:
  • 资助金额:
    $165.13万
  • 财政年份:
    2022
  • 负责人:
    VISHWA DEEP DIXIT
  • 依托单位:
Caloric restriction-driven immunometabolic checkpoints of inflammation
  • 批准号:
    10656332
  • 项目类别:
  • 资助金额:
    $55.01万
  • 财政年份:
    2022
  • 负责人:
    VISHWA DEEP DIXIT
  • 依托单位:
Immunometabolic regulation of bone inflammaging
  • 批准号:
    10430514
  • 项目类别:
  • 资助金额:
    $50.25万
  • 财政年份:
    2022
  • 负责人:
    VISHWA DEEP DIXIT
  • 依托单位: