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
• 负责人: QIUFU MA
• 金额: $ 44.5万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018638
• 关键词: Abdomen; Acupuncture Points; Address; Adrenal Glands; Adrenergic Receptor; Afferent Neurons; Anatomy; Anti-Inflammatory Agents; Attenuated; Automobile Driving; Bacteria; Body Regions; Cells; Chest; Disease; Dissection; Efferent Neurons; Electroacupuncture; Endotoxins; Exposure to; Fatality rate; G-Protein-Coupled Receptors; Genetic; Goals; Hindlimb; Immune; Infection; Inflammation; Inflammatory; Injections; Laboratory Animals; Lead; Lipopolysaccharides; Location; Maps; Modality; Modeling; Molecular; Mus; Nerve; Neural Pathways; Neurons; Neuropeptides; Norepinephrine; Organ; Pathway interactions; Patients; Peripheral; Pilot Projects; Prevention; Reflex action; Regimen; Research; Role; Safety; Sepsis; Series; Signal Transduction; Spinal; Survivors; Sympathetic Nervous System; Testing; Therapeutic; Tissues; United States; base; beta-2 Adrenergic Receptors; cecal ligation puncture; cytokine; genetic approach; hindbrain; improved; innovation; macrophage; neural circuit; noradrenergic; prevent; relating to nervous system; somatosensory; tool

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）（ii）安全性和（iii）神经的可信度 通过定义功能性神经回路来刺激作为败血症的治疗。在美国，有1-3万 每年患有败血症的患者将死亡15-30％，许多冲浪者将遭受器官损害。 传统的治疗方案到目前为止是不足的。在这种背景下，神经刺激（例如 特定穴位上的非侵入性电针刺激（ES）会减弱全身炎症 与败血症相关并促进实验动物的生存。迄今为止，一个主要观点是ES 驱动迷走神经依赖性抗炎途径，涉及交感细胞的激活和 随后对免疫细胞促炎性细胞因子释放的调节。但是，有两个 为了实现ES作为治疗的全部潜力，必须解决的重要未解决的问题必须解决 败血症的方式。首先，同情神经元的作用仍然不明显。去甲肾上腺素（NA），之一 长期以 β2肾上腺素受体的激活。但是，NA还可以通过激活α2促进炎症 肾上腺素受体以及这种促炎的信号传导在巨噬细胞前可能是敏感的 暴露于细菌衍生的内毒素，例如脂多糖（LPS）。根据，它仍然是 未知i）如果败血症发展到某些阶段时，是否可以对ES进行反调查，ii）如果策略 在促炎活性上，最大化抗炎药对于治疗严重败血症是至关重要的。 其次，早就知道ES只能在特定的穴位中驱动迷走神经副交感神经反射， 但是基本的神经基础是完全未知的。由于身份未知和解剖学 驱动迷走神经反射的体感神经元的分布，很难优化刺激 激活此抗炎途径的参数。为了解决这些未解决的问题，我们有 开发了创新的遗传工具来消除，沉默或激活分子定义的交感神经和 体感神经元。基于强烈的初步结果，我们假设i）感官神经元标志着 G蛋白偶联受体PROKR2的表达需要低电强度ES（0.5 mA）至 驱动迷走神经反射，以及ii）甲肾上腺素能交感神经元的表达为 可以通过高强度ES激活的神经肽NPY可以抑制并促进 炎症，取决于败血症表现之前或之后的ES。一系列来自 这些假设将进行检验。在时间的充实中，本申请中概述的研究将使我们能够 图解的不同神经元途径可以动态调节败血症相关的全身注射， 并将通过促进促炎性促进抗炎药来改善败血症的管理 途径。 呢