Role of NF-kB in sympathetic hyperreflexia after spinal cord injury

NF-kB在脊髓损伤后交感神经反射亢进中的作用

• 批准号: 10391321
• 负责人: Micaela Lucy O'Reilly
• 金额: $ 4.68万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391321
• 关键词: Affect; American; Anatomy; Anti-Inflammatory Agents; Attenuated; Autoimmune Diseases; Automobile Driving; Autonomic Dysreflexia; Axon; Bacterial Pneumonia; Biochemical; Biological Assay; Bladder; Blood Pressure; Bradycardia; Cardiovascular Diseases; Cardiovascular system; Cells; Chest; Chronic; Complex; Development; Disease; Dose; Exhibits; FDA approved; Fecal Impaction; Flow Cytometry; Frequencies; Glutamates; Goals; Heart Rate; Hyperreflexia; Hypertension; Immune; Immune System Diseases; Immunologic Deficiency Syndromes; Immunosuppression; Impairment; Individual; Infection; Inflammatory; Inhibition of NF-KB activation; Injury; Interneurons; Interruption; Life; Light; Mediating; Mediator of activation protein; Microglia; Modeling; Morbidity - disease rate; Myocardial Infarction; NF-kappa B; Neuroimmune system; Neuronal Plasticity; Neurons; Organ; Output; Patients; Peripheral; Pharmacology; Phenotype; Population; Predisposition; Production; Property; Proteins; Quality of life; Quantitative Reverse Transcriptase PCR; Reflex action; Regulation; Rheumatoid Arthritis; Risk; Rodent; Role; Secondary to; Severities; Shapes; Signal Transduction; Site; Spinal; Spinal Cord transection injury; Spinal cord injury; Spleen; Stroke; Sulfasalazine; Sympathetic Nervous System; Synapses; Synaptic plasticity; TNF gene; Telemetry; Testing; Therapeutic; Thoracic spinal cord structure; Time; Trauma; Ulcerative Colitis; autocrine; cytokine; decubitus ulcer; glutamatergic signaling; immune function; improved; inhibitor; mortality; neural circuit; neuronal excitability; new therapeutic target; prevent; prophylactic; response; sensory input; sensory stimulus; transcription factor

PROJECT SUMMARY / ABSTRACT Cardiovascular disease and immune dysfunction are the two leading causes of morbidity and mortality in individuals with high-level spinal cord injuries (SCI). This is primarily due to the development of sympathetic hyperreflexia, which is immediately apparent as an episode of autonomic dysreflexia (AD). AD is a condition occurring in up to 90% of patients with SCI above thoracic segment 6 that is characterized by life-threatening hypertension and reflexive bradycardia in response to below-level noxious sensory input. The frequency and severity of AD episodes progressively increase over time and contribute to increased risk for life-threatening infections, myocardial infarction, and stroke. The progressive exacerbation of sympathetic hyperreflexia is thought to be due to maladaptive plasticity within the spinal sympathetic reflex (SSR) circuit which contributes to heightened sensitivity and exaggerated sympathetic output to critical effector organs, such as vasculature and the spleen. This neurogenic sympathetic hyperreflexia thereby impairs peripheral immune function and contributes to systemic immunosuppression that further propagates infection susceptibility. Limiting SSR circuit plasticity and the development of sympathetic hyperreflexia could therefore have enormous therapeutic implications in mitigating injury-induced immunosuppression and greatly improve quality of life in individuals with SCI. Interestingly, the neuroimmune system is implicated as a major underling factor that contributes to the development of SSR circuit plasticity. Specifically, continued activation of resident microglia local and remote to the injury site is associated with the production of various proinflammatory cytokines, including soluble tumor necrosis factor-alpha (sTNFα), that are known to modulate neural circuits. Despite long-term inhibition of sTNFα after SCI, microglia continue to exhibit a reactive phenotype and there is persistent activation of NF-kB, a transcription factor complex that is activated by multiple cytokines, well below the SCI. This suggests that reactive microglia continue to produce a variety of cytokine factors in addition to sTNFα, which continue to activate NF- kB and thereby establish a pro-inflammatory autocrine loop. Furthermore, NF-kB has been implicated as a key mediator in chronic inflammatory disorders, such as rheumatoid arthritis, and directly contributes to synaptic and cellular plasticity. This proposal will focus on the hypothesis that activation of NF-kB after SCI contributes to driving SSR circuit plasticity that results in the development of sympathetic hyperreflexia and associated AD, as well as peripheral immune dysfunction. Moreover, we hypothesize that microglial NF-kB signaling alters neuronal excitability within the SSR circuit. The primary goals of this proposal are to: 1) investigate the role of NF-kB signaling in the development of sympathetic hyperreflexia (indicated by AD) and resultant dysimmunity (Aim 1); 2) elucidate how SCI-induced NF-kB activity in microglia shapes their phenotype and how that influences plasticity of neurons within the SSR circuit (Aim 2).

项目摘要 /摘要 心血管疾病和免疫功能障碍是发病和死亡率的两个主要原因 在具有高级脊髓损伤（SCI）的个体中。这主要是由于同情的发展 超反射症，这是立即显而易见的自主性逆转录病（AD）的发作。广告是一个条件 在胸腔段6上方的SCI患者中最多发生，其特征是威胁生命 高血压和反射性心动过缓，以响应低级有害的感觉输入。频率和 广告发作的严重性随着时间的推移逐渐增加，并导致威胁生命的风险增加 感染，心肌梗塞和中风。交感性超反复反应的逐渐加剧是 被认为是由于脊柱交感反射（SSR）电路内的不良适应性可塑性所致 对关键效应器官（例如脉管系统）和 脾脏。这种神经源性交感性超反射症因此会损害外周免疫功能和 有助于系统性免疫抑制，进一步传播感染易感性。限制SSR电路 因此，可塑性和交感神经高反射症的发展可能具有巨大的治疗 减轻伤害引起的免疫抑制的影响，并大大改善患有患者的生活质量 科学。有趣的是，神经免疫系统被实施是有助于 SSR电路塑性的发展。具体而言，居民持续激活本地小胶质细胞和遥控器 损伤部位与包括实体瘤在内的各种促炎细胞因子的产生有关 已知会调节神经回路的坏死因子-Alpha（STNFα）。尽管长期抑制了STNFα SCI之后，小胶质细胞继续表现出反应性表型，并且NF-KB持续激活A 转录因子复合物被多种细胞因子激活，远低于SCI。这表明反应性 除了STNFα之外，小胶质细胞还会继续产生各种细胞因子因子，该因子继续激活NF- KB，从而建立促炎性自分泌循环。此外，NF-KB被暗示为钥匙 慢性炎症性疾病（例如类风湿关节炎）中的介体，直接有助于突触和 细胞塑性。该提案将重点介绍以下假设：SCI后NF-KB的激活有助于 驱动SSR电路可塑性导致交感神经性超反射和相关的AD的发展 以及外周免疫功能障碍。此外，我们假设小胶质NF-KB信号改变了神经元 SSR电路中的兴奋性。该提案的主要目标是：1）调查NF-KB的作用 交感性超反射症的发展（由AD表示）和由此产生的densimmunity（AIM 1）； 2）阐明SCI诱导小胶质细胞中的NF-KB活性如何塑造其表型及其如何影响 SSR电路内神经元的可塑性（AIM 2）。