Peripheral Trafficking in Locomotor Networks After Thoracic SCI

描述（由申请人提供）：脊髓损伤（SCI）在腰膨大病变尾部至少10个节段引发快速炎症信号。作为远程神经炎症的结果，感觉和运动系统显示永久性缺陷。引发这些远程效应的机制在很大程度上是推测性的。该提案研究了腰髓运动网络周围毒性炎症的新来源，该来源阻碍了基于活动的运动干预。我们将使用GFP+骨髓（BM）嵌合体模型来区分SCI后的居民和外周免疫应答（目的1）。使用NanoString基因阵列分离和表征免疫细胞。此外，我们还将通过血管示踪剂和免疫组织化学检查远端腰椎解剖结构来描述内皮稳定性。为了研究腰部集中运动干预和远程神经炎症之间的细胞和分子相互作用，我们将在SCI后早期（2- 7天）提供训练干预。原理设计证明将用于通过消耗外周单核细胞群体来检查源自外周免疫细胞的神经炎症对基于活性的恢复的影响（目的2）。在整个提案中，我们将在GFP+ BM嵌合小鼠中应用一种新的小鼠模型，该小鼠在Thy-1启动子的控制下在神经元上表达YFP，以通过树突棘组成来检查区域炎症和神经可塑性之间的关系。这一建议得到了强有力的初步证据的支持，即在胸中段脊髓损伤后，整个腰骶髓中至少有13个节段的髓系运输和血管破裂。因此，我们假设胸段脊髓损伤导致远离病变的外周髓细胞运输，从而危及运动网络的功能和可塑性。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) initiates rapid inflammatory signaling at least 10 segments caudal to the lesion in the lumbar enlargement. As a result of remote neuroinflammation, sensory and motor systems display permanent deficits. The mechanisms that initiate these remote effects are largely speculative. This proposal examines a novel source of toxic inflammation around locomotor networks in the lumbar cord that impedes activity-based exercise interventions. We will use a GFP+ bone marrow (BM) chimera model to differentiate between resident and peripheral immune responses after SCI (Aim 1). Immune cells with be isolated and characterized using NanoString gene arrays. Additionally, we will describe endothelial stability by administering vascular tracers and examining remote lumbar anatomy using immunohistochemistry. To examine the cellular and molecular interaction between lumbar-focused exercise interventions and remote neuroinflammation, we will deliver training interventions early (2-7d) after SCI. Proof of principle designs will be used to examine the influence of neuroinflammation derived from peripheral immune cells on activity-based recovery by depleting peripheral monocyte populations (Aim 2). Throughout the proposal, we will apply a novel mouse model in GFP+ BM-chimeric mice that express YFP on neurons under control of the Thy-1 promoter to examine the relationship between regional inflammation and neuroplasticity via dendritic spine composition. The proposal is supported by strong preliminary evidence that myeloid trafficking and vascular breakdown occurs at least 13 segments below the lesion throughout the lumbar and sacral cord after midthoracic SCI. Therefore, we hypothesize that thoracic SCI results in peripheral myeloid trafficking remote to the lesion that jeopardizes function and plasticity of locomotor networks.