Genetic dissection of neural pathways that modulate systemic inflammation

调节全身炎症的神经通路的基因解剖

基本信息

  • 批准号:
    10251945
  • 负责人:
  • 金额:
    $ 44.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-16 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary The broad goal of this research is to improve (i) the potency, (ii) safety, and (iii) the credibility of nerve stimulation as a treatment for sepsis by defining the functional neural circuitry. In the USA, among 1-3 million patients suffering sepsis each year, 15-30% will die and many of the survivors will suffer organ damage. Conventional therapeutic regimens are thus far inadequate. Against this backdrop, nerve stimulations such as non-invasive electroacupuncture stimulation (ES) at specific acupoints can attenuate systemic inflammation associated with sepsis and promote survival of laboratory animals. To date, one dominant view is that ES drives vagal nerve-dependent anti-inflammatory pathways, involving activation of sympathetic cells and subsequent modulation of pro-inflammatory cytokine release from immune cells. However, there are two important unresolved issues that must be addressed in order to realize the full potential of ES as a therapeutic modality for sepsis. First, the roles of sympathetic neurons are still ill-defined. Noradrenaline (NA), one of transmitters released from sympathetic cells, has long been proposed to suppress systemic inflammation, via activation of β2 adrenergic receptors. However, NA can also promote inflammation via activation of α2 adrenergic receptors, and this pro-inflammatory signaling can be sensitized following macrophage pre- exposure to bacteria-derived endotoxins such as the lipopolysaccharide (LPS). Accordingly, it remains unknown i) if ES could be counterindicated when sepsis has progressed to certain stages, and ii) if a strategy to maximize the anti-inflammatory over the pro-inflammatory activity is pivotal for ES to treat severe sepsis. Second, it has been long known that ES can drive vagal parasympathetic reflexes only in specific acupoints, but the underlying neural basis is entirely unknown. Because of unknown identities and anatomical distributions of somatosensory neurons driving vagal reflexes, it becomes difficult to optimize stimulation parameters to activate this anti-inflammation pathway. To address these unresolved issues, we have developed innovative genetic tools to ablate, silence or activate molecularly defined sympathetic and somatosensory neurons. Built upon strong preliminary results, we postulate i) that sensory neurons marked by the expression of the G protein-coupled receptor Prokr2 are required to for low electric intensity ES (0.5 mA) to drive vagal reflexes, and ii) that noradrenergic sympathetic neurons marked by the expression of the neuropeptide NPY, which can be activated by high intensity ES (3 mA), may suppress and promote inflammation, dependent on ES delivered before or after sepsis manifestation. A series of predictions from these hypotheses will be tested. In the fullness of time, the studies outlined in this application will enable us to illustrate distinct neuronal pathways that can dynamically modulate sepsis-associated systemic inflammation, and will help to improve sepsis management by promoting the anti-inflammatory over the pro-inflammatory pathways. !
项目摘要 这项研究的广泛目标是提高(i)效力,(ii)安全性,(iii)神经的可信度 通过定义功能性神经回路,刺激作为脓毒症的治疗。在美国,1 - 3百万人中 每年有15 - 30%的败血症患者会死亡,许多幸存者会遭受器官损伤。 传统的治疗方案远远不够。在这种背景下,神经刺激,如 特定穴位的非侵入性电针刺激(ES)可以减轻全身炎症 与败血症相关,并促进实验室动物的存活。到目前为止,一个主流观点是ES 驱动迷走神经依赖性抗炎通路,涉及交感神经细胞的激活, 随后调节促炎细胞因子从免疫细胞释放。但有两 为了充分发挥ES作为治疗药物的潜力,必须解决的重要未解决问题 脓毒症的模式。首先,交感神经元的作用仍然不明确。去甲肾上腺素(NA), 从交感神经细胞释放的神经递质,长期以来一直被认为可以通过 β 2肾上腺素能受体的激活。然而,NA也可以通过激活α 2 肾上腺素能受体,这种促炎信号可以被敏化后,巨噬细胞前, 暴露于细菌衍生的内毒素,如脂多糖(LPS)。因此, 未知i)当脓毒症进展到某些阶段时,ES是否可以作为反指征,以及ii)如果策略 最大限度地发挥抗炎作用是ES治疗严重脓毒症的关键。 第二,人们早就知道ES只能在特定的穴位驱动迷走副交感神经反射, 但根本的神经基础完全未知由于身份不明和解剖学原因 由于驱动迷走神经反射的体感神经元的分布,因此难以优化刺激 参数来激活这种抗炎途径。为了解决这些悬而未决的问题,我们 开发了创新的遗传工具,以消融,沉默或激活分子定义的交感神经系统, 躯体感觉神经元建立在强有力的初步结果,我们假设i),感觉神经元标记的 G蛋白偶联受体Prokr 2的表达需要低电场强度ES(0.5 mA), 驱动迷走神经反射,和ii)去甲肾上腺素能交感神经元标记的表达, 神经肽NPY可被高强度ES(3mA)激活,可抑制和促进 炎症,依赖于脓毒症表现之前或之后递送的ES。一系列的预测, 这些假设将得到检验。随着时间的推移,本申请中概述的研究将使我们能够 说明了可以动态调节脓毒症相关全身性炎症的不同神经元通路, 并将有助于通过促进抗炎作用而不是促炎作用来改善脓毒症的治疗 途径。 !

项目成果

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QIUFU MA其他文献

QIUFU MA的其他文献

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{{ truncateString('QIUFU MA', 18)}}的其他基金

Genetic dissection of visceral pain pathways
内脏疼痛通路的基因剖析
  • 批准号:
    10379941
  • 财政年份:
    2019
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic dissection of neural pathways that modulate systemic inflammation
调节全身炎症的神经通路的基因解剖
  • 批准号:
    10018638
  • 财政年份:
    2019
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    8103210
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    8489281
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    9094518
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    7321491
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    8889507
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    7651199
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    7477804
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:
Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior
伤害性感觉神经元发育和疼痛行为的遗传控制
  • 批准号:
    7872836
  • 财政年份:
    2007
  • 资助金额:
    $ 44.5万
  • 项目类别:

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Electrical Potential at Acupuncture Points: Using a Novel Biokelvin Probe
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