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

项目摘要/摘要 心血管疾病和免疫功能障碍是发病率和死亡率的两大主要原因。 在患有高度脊髓损伤(SCI)的个体中。这主要是由于同情心的发展。 反射亢进，这是自主神经反射障碍(AD)的一种表现。广告是一种条件 发生在高达90%的胸段以上脊髓损伤患者，其特征是危及生命 高血压和反射性心动过缓对低于水平的伤害性感觉输入的反应。频率和频率 随着时间的推移，AD发作的严重性逐渐增加，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神经反射(SSR)回路中的不适应可塑性导致的 对关键效应器官的高度敏感性和夸大的交感输出，如血管系统和 脾。这种神经源性交感神经反射亢进从而损害外周免疫功能和 有助于全身性免疫抑制，从而进一步传播感染易感性。限制SSR电路 因此，可塑性和交感神经反射亢进的发展可能具有巨大的治疗作用。 对减轻创伤所致免疫抑制和极大提高患者生活质量的意义 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。具体地说，本地和远程驻留的小胶质细胞的持续激活 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。 已知的调节神经回路的肿瘤坏死因子-α(sTNF-α)。尽管s肿瘤坏死因子α长期受到抑制 脊髓损伤后，小胶质细胞继续呈现反应性表型，并持续激活核因子-kB，a 转录因子复合体，由多种细胞因子激活，远低于脊髓损伤。这表明，反应性 除肿瘤坏死因子α外，小胶质细胞继续产生多种细胞因子，从而继续激活核因子-2。 Kb，从而建立一个促炎自分泌循环。此外，核因子-kB被认为是一个关键 在慢性炎症性疾病，如类风湿性关节炎中的介体，并直接参与突触和 细胞可塑性。这项建议将重点放在脊髓损伤后核因子-kB的激活有助于 驱动SSR电路的可塑性，导致交感神经反射亢进和相关的AD，AS 以及外周免疫功能障碍。此外，我们假设小胶质细胞的核因子-kB信号改变了神经元。 SSR电路内的兴奋性。这项提议的主要目标是：1)研究核因子-kB的作用 交感神经反射亢进(AD)和由此引起的免疫功能障碍(目标1)的信号传递； 2)阐明脊髓损伤诱导的小胶质细胞的核因子-kB活性如何影响其表型及其影响。 SSR回路内神经元的可塑性(目标2)。

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).