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. !

项目概要 这项研究的总体目标是提高 (i) 效力、(ii) 安全性和 (iii) 神经的可信度 在美国，有 1-300 万人通过刺激来治疗脓毒症。 每年患有败血症的患者中，有 15-30% 会死亡，许多幸存者会遭受器官损伤。 在此背景下，传统的治疗方案迄今为止还不够。 在特定穴位进行无创电针刺激（ES）可以减轻全身炎症 迄今为止，一种主流观点是 ES 与败血症相关并促进实验动物的存活。 驱动迷走神经依赖性抗炎途径，涉及交感神经细胞的激活和 然而，有两种方法可以随后调节免疫细胞释放促炎细胞因子。 为了充分发挥 ES 作为治疗药物的潜力，必须解决一些尚未解决的重要问题 首先，交感神经元（NA）的作用仍然不明确，它是其中之一。 长期以来，人们一直认为交感细胞释放的递质可以通过以下方式抑制全身炎症： 然而，NA 也可以通过激活 α2 促进炎症。 肾上腺素能受体，这种促炎信号可以在巨噬细胞预 暴露于细菌衍生的内毒素，例如脂多糖（LPS），因此，它仍然存在。 未知 i) 当败血症进展到某些阶段时是否可以取消 ES，以及 ii) 如果有策略 最大限度地提高抗炎活性而不是促炎活性对于 ES 治疗严重脓毒症至关重要。 其次，人们早就知道ES只能在特定的穴位驱动迷走神经副交感神经反射， 但由于身份和解剖学未知，潜在的神经基础完全未知。 驱动迷走神经反射的体感神经元的分布，优化刺激变得困难 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融、沉默或激活分子定义的交感神经和 基于强有力的初步结果，我们假设 i) 感觉神经元标记为 G 蛋白偶联受体 Prokr2 的表达需要低电场强度 ES (0.5 mA) 驱动迷走神经反射，并且 ii) 去甲肾上腺素能交感神经元的表达为 神经肽 NPY 可被高强度 ES (3 mA) 激活，可能会抑制和促进 炎症，取决于脓毒症表现之前或之后递送的 ES 的一系列预测。 随着时间的推移，这些假设将得到检验，本申请中概述的研究将使我们能够 说明可以动态调节脓毒症相关全身炎症的不同神经通路， 并通过促进抗炎而非促炎来帮助改善脓毒症管理 途径。 ！