Multipronged approach to diminish sympathetic hyperreflexia and ensuing cardiovascular and immune dysfunction after spinal cord injury

项目总结 脊髓损伤(SCI)是一种毁灭性的事件，多达130万美国人遭受着这种疾病的折磨。虽然不经常 认识到，心血管疾病和对感染的易感性是死亡率和发病率的主要原因。 患有脊髓损伤的个体。这些问题背后的一个主要原因被认为是脊髓损伤引起的调控失调。 交感神经系统的。在这个方案中，我们将使用与临床相关的挫伤啮齿动物脊髓损伤模型。 为了验证细胞内Sigma多肽(Isp)将促进5-羟色胺能充分萌发的假设 轴突进入脊髓损伤后脊髓交感神经回路中的神经元，使损伤后的交感神经活动正常化。 此外，我们假设联合应用isp和抑制可溶性肿瘤坏死因子 阿尔法(sTNFα)和XPro1595-针对脊髓损伤后交感神经反射亢进的不同根本原因(即， 脊髓上传入中断的脊髓交感神经回路与肿瘤坏死因子α诱导的大鼠适应不良可塑性 脊髓交感神经回路)-将在改善心血管和免疫方面起到协同作用 脊髓损伤后的功能。

PROJECT SUMMARY Spinal cord injury (SCI) is a devastating event sustained by as many as 1.3 million Americans. While not often appreciated, cardiovascular disease and susceptibility to infection are leading causes of mortality and morbidity in individuals living with SCI. One major reason thought to underlie these issues is SCI-induced dysregulation of the sympathetic nervous system. In this proposal, we will use a clinically-relevant contusion rodent SCI model to test the hypothesis that intracellular sigma peptide (ISP) will promote sufficient sprouting of serotonergic axons onto neurons in the spinal sympathetic circuit below the SCI to normalize sympathetic activity after injury. Furthermore, we hypothesize that administering a combining ISP and inhibition of soluble tumor necrosis factor alpha (sTNFα) with XPro1595 – which target different root causes of sympathetic hyperreflexia after SCI (i.e., interrupted supraspinal input the spinal sympathetic circuit and sTNFα-induced maladaptive plasticity of the spinal sympathetic circuit, respectively) – will have synergistic effects on improving cardiovascular and immune function after SCI.