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

项目总结 心血管疾病和易受感染是发病率和死亡率的两个主要原因。 适用于脊髓损伤(SCI)患者。脊髓损伤相关心血管疾病的主要贡献者之一 疾病和免疫缺陷是自主神经反射障碍(AD)综合征，是对 70%-90%的人对损伤以下感觉刺激的自主神经系统反应 他们承受了很高的SCI。AD的特点是极端、突然的高血压和反射性发作。 心动过缓(即心率减慢)。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 分别对心血管疾病和感染易感性有贡献。只是限制AD强度 可能具有显著的治疗价值，改善脊髓损伤患者的整体健康状况。阿尔茨海默病逐渐加重 被认为是由损伤下方回路的可塑性驱动的，这种可塑性导致了夸大的脊髓交感 条件反射。不幸的是，触发这种非适应性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 是异常可塑性和与其他病理相关的过度兴奋回路的潜在因素。 促炎症的可溶型细胞因子肿瘤坏死因子α(sTNFα)被认为与 在许多情况下引发炎症。此外，肿瘤坏死因子α与多种形式的可塑性有关， 可以增加神经元的兴奋性。我们推测脊髓损伤下脊髓中的stfα起着至关重要的作用。 在触发异常可塑性导致脊髓损伤后交感神经回路过度活跃和 阿尔茨海默病的继发性、强化期。此外，这项提议将侧重于sTNFa/TNFR1的假设 参与该回路的神经元中的信号是病情恶化的中心。我们将使用一个 建立了可靠致AD的成年大鼠脊髓胸段3横断模型。整体而言 这一多PI提议的目的是：1)进一步询问抑制sTNFα的治疗潜力 降低AD(AIMS 1)；2)探讨神经细胞sTRANα/TnFR 1介导AD(AIMS)的机制 2和3)。

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).