Synergistic white matter injury from diesel exhaust particulate and chronic cerebral hypoperfusion exposures: Interaction between the Nogo/NgR1 receptor pathway and extravascular fibrinogen toxicity

研究表明，脑灌注不足和血脑屏障（BBB）通透性在脑梗死中起重要作用。 认知障碍和痴呆的发作和进展。环境空气污染可能会对 患有潜在脑血管疾病的个体的认知健康。小鼠研究表明， 颗粒物（PM）暴露和慢性脑灌注不足（CCH）对 皮质下白色物质损伤和神经认知缺陷。该提案利用了细胞培养研究和 小鼠双侧颈动脉狭窄（BCAS）模型，以评估柴油机排气微粒（DEP）的影响 在一个系统中，分离出认知能力下降和痴呆症的纯血管成分。潜在协同作用 轴突生长抑制剂和血管外纤维蛋白原沉积之间的关系被研究为 白色物质损伤与修复。该项目的具体目标是：1）审查Nogo/NgR 1的作用 在DEP暴露后轴突再生和白色物质修复中的作用。2)建立BBB的角色 血管通透性和血管外纤维蛋白原对DEP/CCH后轴突再生和白色损伤的影响 3）检查NgR 1和67 KDa层粘连蛋白受体（67 LR）结合/内化的可能性 治疗策略，以减轻白色物质病理学的DEP/CCH暴露的设置。析因设计 将确定DEP和CCH对白色物质毒性的独立和联合影响， 神经认知我们预计PM暴露引发NgR 1通路抑制神经突生长。我们也 预计PM暴露会增加血浆纤维蛋白原水平。这两种变化都不会产生大量的白色 伤害自己的事。我们预期CCH会放大PM对神经突生长抑制的作用，并且白色 物质毒性。我们假设这将通过1）继发于缺氧的cAMP水平降低， 增强DEP诱导的轴突生长抑制和2）增加BBB通透性，导致血管外 皮质下白色物质中纤维蛋白原沉积。除了引起直接的白色物质毒性外， 纤维蛋白原可通过整合素b3/表皮生长因子受体（EGFR）损害轴突再生 硫酸软骨素蛋白聚糖（CSPGs）增加，可进一步抑制白色物质修复 通过NgR 1途径。我们将评估表没食子儿茶素-3-没食子酸酯（EGCG）给药对 减轻PM和CCH暴露后的白色物质损伤。我们希望通过一个协调的 NgR 1和67 LR结合/内化和cAMP介导的信号传导的策略。

Studies suggest an important role for cerebral hypoperfusion and blood brain barrier (BBB) permeability in the onset and progression of cognitive impairment and dementia. Ambient air pollution may differentially impact cognitive health in individuals with underlying cerebrovascular disease. Murine studies demonstrate that particulate matter (PM) exposure and chronic cerebral hypoperfusion (CCH) have supra-additive effects on subcortical white matter injury and neurocognitive deficits. This proposal leverages cell culture studies and a murine bilateral carotid artery stenosis (BCAS) model to assess the effects of Diesel Exhaust Particulate (DEP) in a system that isolates a purely vascular component of cognitive decline and dementia. Potential synergies between axonal growth inhibitors and extravascular fibrinogen deposition are studied as critical regulators of white matter injury and repair. The specific aims of this project are: 1) Examine the role of the Nogo/NgR1 pathway in axonal regeneration and white matter repair following DEP exposure. 2) Establish the roles of BBB permeability and extravascular fibrinogen on axonal regeneration and white matter injury following DEP/CCH exposures and 3) Examine NgR1 and 67KDa Laminin receptor (67 LR) binding/ internalization as a potential therapeutic strategy to mitigate white matter pathology in the setting of DEP/CCH exposures. A factorial design will determine the independent and combined effects of DEP and CCH on white matter toxicity and neurocognition. We expect PM exposure to prime the NgR1 pathway for neurite outgrowth inhibition. We also expect PM exposure to increase plasma fibrinogen levels. Neither of these changes result in substantial white matter injury on their own. We expect CCH to amplify the PM effects on neurite outgrowth inhibition and white matter toxicity. We hypothesize this will occur through 1) decreased cAMP levels secondary to hypoxia that augment DEP-induced axonal growth inhibition and 2) increased BBB permeability that results in extravascular fibrinogen deposition in the subcortical white matter. In addition to causing direct white matter toxicity, fibrinogen can impair axonal regeneration through the integrin b3/ Epidermal Growth Factor Receptor (EGFR) pathway and increased chondroitin sulfate proteoglycan (CSPGs), which can further inhibit white matter repair through the NgR1 pathway. We will assess the impact of epigallocatechin-3-gallate (EGCG) administration to mitigate white matter injury following PM and CCH exposure. We expect this to work through a coordinated strategy of NgR1 and 67LR binding/ internalization and cAMP mediated signaling.