Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury

项目摘要 据报道，脊髓损伤（SCI）后，没有并发头部损伤的神经心理缺陷; 虽然大多数此类研究反映了患者的自我报告，但更正式的神经心理学测试 表现出与痴呆症相关的高风险表现障碍，包括学习缺陷 和记忆另一方面，患有痴呆症的患者，例如由阿尔茨海默病（AD）引起的患者， 可能有更高的福尔斯风险，因此增加了SCI的风险。很少有研究涉及潜在的 这种神经精神变化的机制或其对靶向治疗的影响。目前迫切 需要这样的研究，因为创伤后痴呆症，如认知和精神变化的负面影响 康复和损害恢复。这项研究的目的是确定负责的机制， 这些不太好的研究，但重要的后果SCI和测试的假设，SCI触发 大脑中CCL 21的释放有助于神经炎症的扩散和认知功能障碍， 抑郁样行为，这可以通过靶向神经炎症的特定机制来改善。 我们将使用转基因小鼠和分子干预来描述CCL 21作为一个关键的作用。 脊髓损伤中脑小胶质细胞活化的调节因子及相关的下游损伤机制目标1将确定 SCI诱导的CCL 21升高介导了大脑中有害的小胶质细胞活化， NOX 2活性。对小胶质细胞活化的多项定量评估将与 靶向CCL 21的分子/遗传干预，以检验SCI诱导的CCL 21释放的假设。 大脑的关键区域通过NOX 2活性导致有害的小胶质细胞激活。目标2将 证明了CCL 21/NOX 2的遗传耗竭或药理学抑制降低了 有害的小胶质细胞激活，导致改善认知能力下降和抑郁样 行为将使用免费的药理学、分子学和遗传学方法来检测 SCI后脑CCL 21/NOX 2介导炎症导致慢性神经退行性变假说 与认知能力下降和抑郁样行为有关。目标3将决定基因或 SCI后的药物小胶质细胞消融减少了脑神经炎症， 改善功能恢复。使用遗传学或药理学小胶质细胞缺失，我们将检查 常驻小胶质细胞在SCI介导的脑神经炎症和功能结局中的作用。 从这些研究中获得的信息将产生重要的积极影响， SCI后重要但在很大程度上被忽视的大脑变化的关键机制， 治疗干预。

Project Summary Neuropsychological deficits have been reported after spinal cord injury (SCI) without concurrent head injury; although most such studies reflect patient self-reports, more formal neuropsychological testing has demonstrated performance impairments with an associated high risk of dementia including deficits in learning and memory. On the other hand, patients with dementia, such as that resulting from Alzheimer’s disease (AD), could have higher risk of falls, and therefore increased risk of SCI. Little research has addressed potential mechanisms for such neuropsychiatric changes or their implications for targeted therapy. There is an urgent need for such studies, as posttraumatic dementia such as cognitive and psychiatric changes negatively impact rehabilitation and impair recovery. The purpose of this study is to identify the mechanisms responsible for these less well examined yet important consequences of SCI and test the hypothesis that SCI-triggered release of CCL21 in the brain contributes to spreading neuroinflammation with cognitive dysfunction and depressive-like behavior, which can be improved by targeting specific mechanisms of neuroinflammation. We will use transgenic mice and molecular interventions to delineate the role of CCL21 as a key regulator of brain microglial activation and related down-stream injury mechanisms in SCI. Aim 1 will identify that SCI-induced CCL21 elevation mediates detrimental microglial activation in the brain through NOX2 activity. Multiple quantitative assessments of microglia activation will be combined with a molecular/genetic intervention targeting CCL21 to test the hypothesis that SCI-induced release of CCL21 in key regions of the brain contributes to detrimental microglial activation through NOX2 activity. Aim 2 will demonstrate that genetic depletion or pharmacological inhibition of CCL21/NOX2 reduces detrimental microglial activation, resulting in improved cognitive decline and depressive-like behavior. Complimentary pharmacological, molecular, and genetic approaches will be used to test the hypothesis that brain CCL21/NOX2-mediated inflammation after SCI causes chronic neurodegeneration associated with cognitive decline and depressive-like behavior. Aim 3 will determine that genetic or pharmacological microglial ablation after SCI reduces brain neuroinflammation leading to improved functional recovery. Using genetic or pharmacological microglia-deletion, we will examine the role of resident microglia in SCI-mediated neuroinflammation in the brain and functional outcomes. The information gained from these studies would have an important positive impact by identifying the key mechanisms involved in important yet largely ignored brain changes after SCI and identifying potential therapeutic interventions.