Soluble TNFa in the development of autonomic dysreflexia after spinal cord injury

可溶性 TNFa 在脊髓损伤后自主神经反射异常发展中的作用

• 批准号: 9902562
• 负责人: John Roland Bethea
• 金额: $ 57.09万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902562
• 关键词: Adult; Affect; Afferent Neurons; American; Anatomy; Attenuated; Autonomic Dysreflexia; Autonomic nervous system; Biological; Biological Assay; Blood Pressure; Blood Vessels; Bradycardia; Cardiovascular Diseases; Cardiovascular system; Cells; Chest; Chronic; Complex; Data; Development; Disease; Disease susceptibility; Electrophysiology (science); Event; Flow Cytometry; Glutamates; Goals; Health; Heart Rate; Hyperactive behavior; Hyperreflexia; Hypertension; Immune; Immune System Diseases; Immunosuppression; Individual; Infection; Inflammation; Inflammatory; Infusion procedures; Injury; Interneurons; Lead; Lesion; Life; Link; Mediating; Modeling; Morbidity - disease rate; NF-kappa B; NFKB Signaling Pathway; Neuroglia; Neuroimmune system; Neurons; Nociception; Pathology; Peripheral; Phase; Play; Process; Prophylactic treatment; Public Health; Rattus; Reaction; Reflex action; Rodent; Role; Severities; Signal Transduction; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Syndrome; TNF gene; TNFRSF1A gene; Telemetry; Testing; Therapeutic; Thoracic spinal cord structure; Time; Tissues; Vascular Diseases; base; cell type; cytokine; factor A; immune function; improved; inhibitor/antagonist; injured; mature animal; mortality; neural circuit; neuronal excitability; prophylactic; receptor; response; sensory stimulus

PROJECT SUMMARY Cardiovascular disease and susceptibility to infection are two leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). One of the major contributors to SCI-associated cardiovascular disease and immune deficiency is the syndrome autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system in response to sensory stimuli below the injury that manifests in 70%-90% of people who have sustained a high SCI. AD is hallmarked by extreme, sudden bouts of hypertension and reflexive bradycardia (i.e. heart rate decrease). Over time, AD events become more severe. These chronic, frequent episodes of hypertension are thought to lead to peripheral vascular dysfunction and immune suppression that contribute to cardiovascular disease and susceptibility to infection, respectively. Merely limiting AD intensity may have significant therapeutic value and improve SCI patients' overall health. The gradual exacerbation of AD is thought to be driven by plasticity of circuits below the lesion that results in an exaggerated spinal sympathetic reflex. Unfortunately, the mechanisms that trigger this maladaptive plasticity are still poorly understood, limiting the development of prophylactic treatments. Interestingly, an activated neuroimmune system is thought to be an underlying factor in aberrant plasticity and hyperexcitable circuits correlated with other pathologies. The pro-inflammatory, soluble form of the cytokine tumor necrosis factor α (sTNFα) has been implicated in initiating inflammation in many contexts. Furthermore, sTNFα is associated with various forms of plasticity that could increase neuronal excitability. We hypothesize that sTNFα in spinal cord below a SCI plays a crucial role in triggering aberrant plasticity that leads to hyperactivity of the spinal sympathetic circuit after SCI and the secondary, intensification phase of AD. Moreover, this proposal will focus on the hypothesis that sTNFa/TNFR1 signaling in neurons involved in the circuit is central to the exacerbation. We will test our hypotheses using an established adult rodent spinal cord thoracic level 3 transection model that reliably results in AD. The overall goals of this multi-PI proposal are to: 1) further interrogate the therapeutic potential of inhibiting sTNFα to reduce AD (Aim 1); 2) investigate the mechanisms underlying how neuronal sTNFα/TNFR1 mediates AD (Aims 2 and 3).

项目摘要 心血管疾病和感染易感性是发病率和死亡率的两个主要原因 脊髓损伤（SCI）的患者。SCI相关心血管疾病的主要贡献者之一 疾病和免疫缺陷是综合征自主神经反射异常（AD），放大反应的 自主神经系统对感觉刺激的反应低于损伤，表现在70%-90%的人 他们都有严重的脊髓损伤AD的特征是极端的、突然的高血压发作和反射性的 心动过缓（即心率降低）。随着时间的推移，AD事件变得更加严重。这些慢性的，频繁的 高血压的发作被认为会导致外周血管功能障碍和免疫抑制， 分别导致心血管疾病和感染易感性。仅限制AD强度 可能具有显著的治疗价值，并改善SCI患者的整体健康状况。AD的逐渐加重 被认为是由病变下方回路的可塑性驱动的， 反射。不幸的是，触发这种适应不良可塑性的机制仍然知之甚少， 限制了预防性治疗的发展。有趣的是，被激活的神经免疫系统被认为 是与其他病理相关的异常可塑性和过度兴奋回路的潜在因素。 促炎的可溶性细胞因子肿瘤坏死因子α（sTNFα）与 在许多情况下引发炎症。此外，sTNFα与各种形式的可塑性有关， 可以增加神经元的兴奋性。我们推测脊髓损伤后sTNFα在脊髓损伤中起重要作用 在触发导致脊髓损伤后脊髓交感神经回路过度活跃的异常可塑性方面， AD的第二个强化阶段。此外，该提议将集中于sTNFa/TNFR 1 参与回路的神经元中的信号传导是恶化的中心。我们将使用一个 建立了成年啮齿动物脊髓胸3级横断模型，可靠地导致AD。整体 该多PI提案的目标是：1）进一步探讨抑制sTNFα的治疗潜力， 2）研究神经元sTNFα/TNFR 1介导AD的机制（目的 第2和第3段）。