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

项目概要 脊髓损伤 (SCI) 是一种毁灭性的事件，有多达 130 万美国人遭受过这种灾难。虽然不经常 众所周知，心血管疾病和感染易感性是死亡率和发病率的主要原因 SCI 患者。造成这些问题的主要原因之一是 SCI 引起的失调 交感神经系统。在本提案中，我们将使用临床相关的挫伤啮齿动物 SCI 模型 检验细胞内 sigma 肽 (ISP) 将促进血清素能充分萌发的假设 轴突连接到 SCI 下方脊髓交感神经回路的神经元上，以使损伤后交感神经活动正常化。 此外，我们假设联合使用 ISP 和抑制可溶性肿瘤坏死因子 α (sTNFα) 与 XPro1595 – 针对 SCI 后交感神经反射亢进的不同根本原因（即 脊髓上交感神经回路的脊髓上输入中断和 sTNFα 诱导的适应不良可塑性 分别）——对改善心血管和免疫有协同作用 SCI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.