Targeting macrophage maladaptation for bacterial sepsis treatment

针对细菌性脓毒症治疗的巨噬细胞适应不良

基本信息

  • 批准号:
    10759684
  • 负责人:
  • 金额:
    $ 30万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-15 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Summary. Sepsis results in massive loss of life and places a significant economic burden on society. There are no effective treatments available for human sepsis other than antibiotics and life support. It is increasingly clear that sepsis is a bi-phasic process comprised of 1) an early high-energy demanding hyperinflammation state that can cause inflammatory shock and 2) a low energy supply immunosuppression state that promotes immunometabolic paralysis while countering oxidative damage. These two phases are seamlessly connected or even concurrent. This makes sepsis treatment extremely difficult, and many therapies such as anti- inflammatory corticosteroids often worsen the outcome. Macrophages (MΦs) play essential roles throughout the course of sepsis. In the hyperinflammation phase, MΦs sense pathogen-associated molecular patterns (PAMPs) through receptors such as toll-like receptors (TLRs) and NOD-, LRP-, and pyrin domain-containing protein 3 (NLRP3). MΦ NLRP3 inflammasome activation and resulting IL-1β secretion cause acute organ damage and release of damage-associate molecular patterns (DAMPs), which act back on the inflammatory pathways, forming a vicious cycle. Therefore, the MΦ NLRP3 inflammasome is a major contributor to the hyperinflammation phase of bacterial sepsis. Concomitant with inflammasome activation, MΦs undergo a broad cellular metabolic rewiring that favors glycolysis and turns mitochondria from ATP generation to reactive oxygen species (ROS) production, leading to mitochondrial oxidative stress, metabolic paralysis, and MΦ anergy in the immunosuppression phase. In addition, NLRP3 inflammasome activation results in GSDMD- mediated pyroptotic cell death (pyroptosis), directly removing MΦs from the fight against secondary infections. Recently, we identified that in MΦs, pyruvate dehydrogenase kinase 1 (PDHK1) plays a critical role in coordinating inflammasome activation and metabolic rewiring. In MΦs treated with LPS and ATP or Nigericin to stimulate inflammasome activation, dichloroacetate (DCA, a pyruvate analog and pan-PDHK inhibitor) or JX06 (a synthetic small-molecule and selective PDHK1 inhibitor) effectively suppressed IL-1β secretion and cell death, improved mitochondrial integrity, and reprogramed mitochondria from ROS production to ATP generation. In a mouse cecal ligation and puncture (CLP) model, PDHK inhibition significantly reduced plasma IL-1β levels. In this STTR Phase 1 project, we will test the hypothesis that JX06 can be developed as a novel therapy for bacterial sepsis. We propose two specific aims: SA1. To determine the toxicity of JX06 in cultured primary mouse and human cells in vitro and mice in vivo, and to study its pharmacokinetics in mice. SA2. To establish the effectiveness of JX06 in various mouse strains using the CLP model of sepsis. This STTR Phase 1 project will validate the role of MΦ PDHK1 in bacterial sepsis and provide a proof of concept to develop JX06 or its analog as a new therapeutic agent for bacterial sepsis. The successful completion of these proposed studies will serve as a milestone for the further development effort.
总结。败血症造成大量生命损失,给社会带来巨大的经济负担。那里 除了抗生素和生命支持外,没有有效的治疗方法来治疗人类败血症。它越来越多地 明确脓毒症是一个双相的过程,包括1)早期的高能量要求的过度炎症 可引起炎症性休克的状态和2)低能量供应的免疫抑制状态,促进 免疫代谢瘫痪,同时对抗氧化损伤。这两个阶段是无缝连接的。 甚至是同时发生的。这使得脓毒症的治疗变得极其困难,许多治疗方法如抗感染 炎症性皮质类固醇往往会使预后恶化。巨噬细胞(MΦS)在整个过程中起着至关重要的作用 败血症的病程。在炎症高发期,MΦS感知病原体相关分子模式 (PAMPS)通过Toll样受体(TLRs)和含有NOD、LRP和PYRIN结构域的受体 蛋白3(NLRP3)。MΦNLRP3炎症小体激活及由此产生的IL-1β分泌导致急性器官 损伤和释放损伤相关的分子模式(DAMP),它对炎症起作用 路径,形成恶性循环。因此,MΦNLRP3炎性小体是导致 细菌败血症的炎症期。伴随着炎症小体的激活,MΦS经历了一次 广泛的细胞代谢重排,有利于糖酵解,并将线粒体从ATP生成转变为活性 氧物种(ROS)的产生,导致线粒体氧化应激、代谢瘫痪和MΦ 处于免疫抑制阶段的无能。此外,NLRP3炎症体激活导致GSDMD- 介导的嗜热性细胞死亡(上睑下垂),直接将MΦS从抵抗二次感染的战斗中移除。 最近,我们发现在MΦS体内,丙酮酸脱氢酶1(PDHK1)在 协调炎症小体的激活和新陈代谢的重新连接。在MΦ中,S用脂多糖和三磷酸腺苷或尼格列星治疗 刺激炎症体激活,二氯乙酸酯(DCA,一种丙酮酸类似物和泛PDHK抑制剂)或JX06 (一种人工合成的小分子选择性PDHK1抑制剂)有效地抑制IL-1β的分泌和细胞 死亡,改善线粒体的完整性,并将线粒体从ROS产生重新编程为ATP 一代。在小鼠盲肠结扎和穿孔(CLP)模型中,抑制PDHK显著降低血浆浓度 IL-1β水平。在这个STTR第1阶段项目中,我们将测试JX06可以作为一种新的 细菌性败血症的治疗。我们提出了两个具体目标:SA1。JX06对体外培养细胞的毒性测定 原代培养小鼠和人细胞,并研究其在小鼠体内的药代动力学。SA2.至 利用CLP脓毒症模型建立JX06对不同品系小鼠的治疗效果。此STTR阶段 1个项目将验证MΦPDHK1在细菌败血症中的作用,并为开发JX06提供概念验证 或其类似物作为一种治疗细菌性败血症的新药物。圆满完成这些拟议的 研究将成为进一步开发工作的里程碑。

项目成果

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Xuewei Zhu其他文献

Xuewei Zhu的其他文献

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{{ truncateString('Xuewei Zhu', 18)}}的其他基金

The role of SLC37A2, a glucose 6 phosphate transporter, in inflammation and metabolic diseases
SLC37A2(一种葡萄糖 6 磷酸转运蛋白)在炎症和代谢疾病中的作用
  • 批准号:
    9234061
  • 财政年份:
    2016
  • 资助金额:
    $ 30万
  • 项目类别:
The role of SLC37A2, a glucose 6 phosphate transporter, in inflammation and metabolic diseases
SLC37A2(一种葡萄糖 6 磷酸转运蛋白)在炎症和代谢疾病中的作用
  • 批准号:
    9082317
  • 财政年份:
    2016
  • 资助金额:
    $ 30万
  • 项目类别:
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作者:{{ showInfoDetail.author }}

知道了