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

研究表明脑低灌注和血脑屏障(BBB)通透性在脑出血中起重要作用。 认知障碍和痴呆症的发病和发展。环境空气污染可能会产生不同的影响 潜在脑血管疾病患者的认知健康状况。小鼠研究表明 颗粒物(PM)暴露和慢性脑低灌流(CCH)对 皮质下白质损伤和神经认知缺陷。这一建议利用了细胞培养研究和 小鼠双侧颈动脉狭窄模型评价柴油机尾气颗粒物(DEP)的作用 在一个隔离认知衰退和痴呆症的纯血管成分的系统中。潜在的协同效应 轴突生长抑制物和血管外纤维蛋白原沉积之间的关系被研究为 脑白质损伤与修复。这一项目的具体目标是：1)审查Nogo/NgR1的作用 DEP暴露后轴突再生和白质修复的途径。2)确定BBB的角色 通透性和血管外纤维蛋白原对DEP/CCH后轴突再生和脑白质损伤的影响 暴露和3)检测NgR1和67 KDa层粘连蛋白受体(67 LR)结合/内化作为一种潜在的 减轻DEP/CCH暴露环境中脑白质病理的治疗策略。析因设计 将确定DEP和CCH对白质毒性和 神经认知。我们预计PM暴露将启动NgR1通路，以抑制轴突生长。我们也 预计PM暴露会增加血浆纤维蛋白原水平。这两个变化都不会产生实质性的白色 物质伤害就靠自己了。我们期望CCH能放大PM对神经突起生长抑制和白蛋白的影响 物质毒性。我们假设这将通过1)缺氧继发的cAMP水平下降而发生 增强DEP诱导的轴突生长抑制和2)增加血脑屏障通透性导致血管外 皮质下白质内纤维蛋白原沉积。除了造成直接的脑白质毒性外， 纤维蛋白原通过整合素b3/表皮生长因子受体(EGFR)损害轴突再生 途径和增加的硫酸软骨素蛋白多糖(CSPGs)，可进一步抑制白质修复 通过NgR1途径。我们将评估表没食子儿茶素没食子酸酯(EGCG)给药对 减轻PM和CCH暴露后的脑白质损伤。我们预计这将通过一个协调一致的 NgR1和67LR的结合/内化策略和cAMP介导的信号转导。

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.