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).

项目概要/摘要 心血管疾病和免疫功能障碍是发病和死亡的两个主要原因 患有高度脊髓损伤（SCI）的个体。这主要是由于交感神经的发展 反射亢进，表现为自主神经反射异常 (AD) 的发作。 AD是一个条件 高达 90% 的胸段 6 以上 SCI 患者会发生这种情况，其特点是危及生命 高血压和反射性心动过缓对低于水平的有害感觉输入的反应。频率和 AD 发作的严重程度随着时间的推移逐渐增加，并导致危及生命的风险增加 感染、心肌梗塞和中风。交感神经反射亢进的进行性加重是 被认为是由于脊髓交感反射（SSR）回路内的适应不良可塑性导致 对关键效应器官（例如脉管系统和神经系统）的敏感性提高和交感神经输出夸大 脾脏。这种神经源性交感神经反射亢进会损害外周免疫功能， 有助于全身免疫抑制，进一步传播感染易感性。限流SSR电路 因此，交感神经反射亢进的可塑性和发展可能具有巨大的治疗作用 减轻损伤引起的免疫抑制并大大改善患有此病的个体的生活质量 SCI。有趣的是，神经免疫系统被认为是导致 SSR电路可塑性的发展。具体来说，持续激活本地和远程的常驻小胶质细胞 损伤部位与各种促炎细胞因子的产生有关，包括可溶性肿瘤 坏死因子-α (sTNFα)，已知可调节神经回路。尽管长期抑制 sTNFα SCI 后，小胶质细胞继续表现出反应表型，并且 NF-kB 持续激活， 由多种细胞因子激活的转录因子复合物，远低于 SCI。这表明反应性 除了sTNFα之外，小胶质细胞继续产生多种细胞因子，持续激活NF- kB，从而建立促炎自分泌环路。此外，NF-kB 被认为是一个关键因素。 慢性炎症性疾病（如类风湿性关节炎）的介质，并直接有助于突触和 细胞的可塑性。该提案将重点关注 SCI 后 NF-kB 激活有助于 驱动 SSR 电路可塑性，导致交感神经反射亢进和相关 AD 的发展，如 以及周围免疫功能障碍。此外，我们假设小胶质细胞 NF-kB 信号传导改变神经元 SSR 电路内的兴奋性。该提案的主要目标是：1）研究 NF-kB 的作用 交感神经反射亢进（AD 所示）和由此产生的免疫失调（目标 1）发展过程中的信号转导； 2) 阐明小胶质细胞中 SCI 诱导的 NF-kB 活性如何塑造其表型以及如何影响 SSR 回路内神经元的可塑性（目标 2）。