Peripheral Trafficking in Locomotor Networks After Thoracic SCI

描述（由申请人提供）：脊髓损伤（SCI）在腰椎肿大时，在病变尾部至少10节段启动快速炎症信号。由于远端神经炎症，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。本研究探讨了腰椎运动网络周围的毒性炎症的新来源，它阻碍了基于活动的运动干预。我们将使用GFP+骨髓（BM）嵌合体模型来区分脊髓损伤后的常驻和外周免疫反应（目的1）。利用纳米串基因阵列对免疫细胞进行分离和表征。此外，我们将通过施用血管示踪剂和使用免疫组织化学检查远端腰椎解剖来描述内皮稳定性。为了研究以腰椎为中心的运动干预与远端神经炎症之间的细胞和分子相互作用，我们将在脊髓损伤后早期（2-7天）进行训练干预。原理证明设计将用于通过消耗外周单核细胞群来检查源自外周免疫细胞的神经炎症对基于活动的恢复的影响（目的2）。在整个提案中，我们将应用一种新的小鼠模型，在Thy-1启动子控制的神经元上表达YFP的GFP+ bm嵌合小鼠，通过树突棘组成来研究区域炎症与神经可塑性之间的关系。强有力的初步证据支持了这一建议，即在中胸椎脊髓损伤后，髓系运输和血管破裂发生在整个腰椎和骶脊髓病变以下至少13节段。因此，我们假设胸椎脊髓损伤会导致远离病灶的外周髓细胞运输，从而损害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.