The ion channel TRPA1 is required for suppression of inflammation in sepsis

离子通道 TRPA1 是抑制脓毒症炎症所必需的

基本信息

批准号：
10356812
负责人：
Sangeeta S. Chavan
金额：
$ 33.5万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356812
关键词：
Acetylcholine Action Potentials Activated Lymphocyte Activation Analysis Address Afferent Neurons Agonist Animals Ankyrin Repeat Anti-Inflammatory Agents Binding Binding Proteins Biological Assay Brain Brain Stem Calcium Cause of Death Cells Clinical Trials Data Disease Disease Progression Electric Stimulation Electrophysiology (science)Endotoxemia Fiber Functional disorder Generations Homeostasis Immune Immune response Immune system Immunohistochemistry Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Interleukin-1 Ion Channel Knockout Mice Knowledge Ligation Measurement Mediating Medical Methods Modality Molecular Motor Mouse Strains Mus Nerve Nerve Fibers Nervous System control Neuroimmune Neurons Neurotransmitters Nicotinic Receptors Organ Pathogenesis Pathway interactions Patients Peripheral Play Prevention Production Proteins Public Health Reflex action Research Research Design Rheumatoid Arthritis Rodent Model Role Sensory Sepsis Septic Shock Signal Transduction Spleen Structure of splenic vein Surface Plasmon Resonance TNF gene TRPA channel Testing Therapeutic Time Transgenic Organisms Travel United States Vagus nerve structure Visceral base brain pathway calcium indicator cytokine design experimental study immunoregulation improved innovation insight macrophage mind control monocyte neural circuit neurophysiology neurotransmission neurotransmitter release novel novel strategies novel therapeutics patch clamp polymicrobial sepsis receptor relating to nervous system response therapeutic target tool

项目摘要

Abstract Sepsis represents a huge unmet medical need: it annually afflicts nearly 1 million individuals in the United States, killing >200,000. The pathophysiology of sepsis and other inflammatory disorders is mediated by dysregulated innate immune responses and abnormally elevated cytokine levels. The inflammatory reflex consists of a neural-immune circuit composed of sensory (afferent) and motor (efferent) vagal neurons that regulate cytokine production in the spleen. The molecular mechanisms of the motor arc are well defined, but considerably less is known about the sensory arc of the inflammatory reflex. In the motor arc, action potentials arise in the vagus nerve, travel in the splenic nerve, and culminate on lymphocytes that are activated to produce acetylcholine, a neurotransmitter molecule that inhibits cytokine production via signaling through 7 nicotinic acetylcholine receptor (7nAChR), expressed on macrophages and monocytes. Using novel electrophysiological recording and decoding methods, we recently identified cytokine-specific sensory neural signals in the vagus nerve. These studies revealed a novel role for an ion channel, transient receptor potential ankyrin-repeat 1 (TRPA1), in the afferent vagus nerve response to IL-1, and selective activation of TRPA1 afferent fibers in the vagus nerve, which also suppresses TNF levels in endotoxemia. Here, we hypothesize that TRPA1 plays an essential role in mediating interleukin-1 (IL-1)-induced vagus nerve activation, and selective stimulation of TRPA1 expressing vagus nerve fibers will improve survival and pathophysiology in sepsis. This hypothesis will be addressed in the following two Specific Aims: Specific Aim 1. Elucidate the role of TRPA1 in mediating IL-1-induced activation of the inflammatory reflex. Specific Aim 2. Assess the dynamics of vagus nerve activity and evaluate the effects of selective TRPA1 stimulation on survival and pathophysiology in sepsis. We propose to utilize a novel approach that integrates experiments assessing direct binding and colocalization of TRPA1 with IL-1Rs on the sensory neurons, analysis of action potential generation in neurons, and evaluating the role of TRPA1-dependent pathophysiological effects in animals subjected to sepsis. This significant new research will provide novel and impactful data for an innovative molecular mechanism of the afferent (sensory) arc of the inflammatory reflex and its role in sepsis. This data will pave the way to develop novel therapeutic modalities for the prevention and treatment of sepsis/septic shock.

抽象的脓毒症代表了一个巨大的未满足的医疗需求：每年有近 100 万人遭受脓毒症的折磨。美国，导致超过 200,000 人死亡。败血症和其他炎症的病理生理学。疾病是由先天免疫反应失调和异常升高介导的炎症反射由感觉组成的神经免疫回路组成。（传入）和运动（传出）迷走神经元调节脾脏中细胞因子的产生。电机电弧的分子机制已得到很好的定义，但人们对电机电弧的分子机制知之甚少。炎症反射的感觉弧在运动弧中，迷走神经中出现动作电位。神经，在脾神经中传播，最终到达被激活的淋巴细胞，产生乙酰胆碱，一种神经递质分子，通过信号传导抑制细胞因子的产生 α7 烟碱乙酰胆碱受体 (α7nAChR)，在巨噬细胞和单核细胞上表达。使用新颖的电生理记录和解码方法，我们最近发现这些研究揭示了迷走神经中细胞因子特异性感觉神经信号的新作用。对于离子通道，瞬时受体电位锚蛋白重复序列 1 (TRPA1)，位于传入迷走神经中对 IL-1 的神经反应，以及迷走神经中 TRPA1 传入纤维的选择性激活，在此，我们研究了 TRPA1 的作用。在介导白细胞介素 1 (IL-1) 诱导的迷走神经激活中发挥重要作用，并且选择性刺激表达迷走神经纤维的 TRPA1 将改善患者的存活率和病理生理学该假设将在以下两个具体目标中得到解决：具体目标 1。阐明 TRPA1 在介导 IL-1 诱导的炎症反射激活中的作用。具体目标 2. 评估迷走神经活动的动态并评估选择性的效果 TRPA1 刺激对脓毒症患者生存和病理生理学的影响我们建议利用一种新颖的方法。该方法将评估 TRPA1 的直接结合和共定位的实验与感觉神经元上的 IL-1R、神经元动作电位生成的分析和评估 TRPA1 依赖性病理生理学效应在患有败血症的动物中的作用。重要的新研究将为创新分子提供新颖且有影响力的数据炎症反射传入（感觉）弧的机制及其在脓毒症中的作用。将为开发新的治疗方法来预防和治疗铺平道路败血症/败血性休克。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions.

有针对性的外周聚焦超声刺激可减轻肥胖引起的代谢和炎症功能障碍。

DOI：
发表时间：
2021
期刊：
影响因子：
4.6
作者：
Huerta, Tomás S;Devarajan, Ale;Tsaava, Tea;Rishi, Arvind;Cotero, Victoria;Puleo, Christopher;Ashe, Jeffrey;Coleman, Thomas R;Chang, Eric H;Tracey, Kevin J;Chavan, Sangeeta S
通讯作者：
Chavan, Sangeeta S

Control of inflammation using non-invasive neuromodulation: past, present and promise.

使用非侵入性神经调节控制炎症：过去、现在和前景。