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

柴油机尾气颗粒和慢性脑灌注不足导致的协同白质损伤：Nogo/NgR1 受体途径与血管外纤维蛋白原毒性之间的相互作用

• 批准号: 10591353
• 负责人: RAYUDU GOPALAKRISHNA
• 金额: $ 235.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591353
• 关键词: Affect; Air Pollution; Alzheimer' s Disease; Astrocytes; Attenuated; Bilateral; Binding; Biological Models; Blood - brain barrier anatomy; Carotid Artery Diseases; Carotid Stenosis; Cell Culture Techniques; Cerebrovascular Disorders; Chondroitin Sulfate Proteoglycan; Chronic; Cognition Disorders; Cognitive; Cyclic AMP; Data; Dementia; Deposition; Diesel Exhaust; Environment; Epidermal Growth Factor Receptor; Epigallocatechin Gallate; Exposure to; Fibrin; Fibrinogen; Functional disorder; Genes; Genetic; Green tea; Growth Cones; Growth Inhibitors; Health; Hypoxia; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Integrins; Joints; Laminin Receptor; Mediating; Modeling; Mus; Myelin; Neurites; Neurocognition; Neurocognitive Deficit; Neurologic; Neuronal Injury; Neurons; Particulate; Particulate Matter; Pathology; Pathway interactions; Pericytes; Peripheral; Pharmacology; Phosphorylation; Plasma; Production; Publishing; RTN4 gene; Rodent; Role; Secondary to; Signal Transduction; Stroke; Sum; System; Therapeutic; Time; Toxic effect; Vascular Cognitive Impairment; Work; ambient air pollution; aquaporin 4; axon growth; axon regeneration; blood-brain barrier permeabilization; cell type; cerebral hypoperfusion; cerebrovascular; dementia risk; design; extracellular; hypoperfusion; injury and repair; mouse model; neurite growth; neuroprotection; polyphenol; receptor; receptor binding; receptor internalization; repaired; response; synergism; systemic inflammatory response; vascular cognitive impairment and dementia; vascular factor; white matter; white matter injury

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.

研究表明，脑灌注灌注和血脑屏障（BBB）渗透性的重要作用 认知障碍和痴呆症的发作和进展。环境空气污染可能会差异影响 潜在的脑血管疾病患者的认知健康。鼠研究表明 颗粒物（PM）暴露和慢性脑灌注灌注（CCH）对上添加的影响对 皮质下白质损伤和神经认知缺陷。该建议利用细胞培养研究和 鼠双侧颈动脉狭窄（BCAS）模型评估柴油排气颗粒的影响（DEP） 在分离出认知能力下降和痴呆症的纯血管成分的系统中。潜在的协同作用 在轴突生长抑制剂和血管外纤维蛋白原沉积之间被研究为关键调节剂 白质伤害和维修。该项目的具体目的是：1）检查Nogo/NGR1的作用 Dep暴露后，轴突再生和白质修理的途径。 2）确定BBB的角色 DEP/CCH后轴突再生和白质损伤的渗透性和血管外纤维蛋白原 暴露和3）检查NGR1和67KDA层粘连蛋白受体（67 LR）结合/内在化 在DEP/CCH暴露的情况下减轻白质病理学的治疗策略。阶乘设计 将确定DEP和CCH对白质毒性的独立和综合影响以及 神经认知。我们预计PM暴露于神经突生长抑制的NGR1途径。我们也是 预计PM暴露会增加血浆纤维蛋白原水平。这些变化都没有导致大量白色 物质伤害自己。我们希望CCH会扩大对神经突生长抑制和白色的影响 物质毒性。我们假设这将通过1）1）降低了继发于缺氧的营地水平 增强DEP诱导的轴突生长抑制和2）增加BBB渗透性，导致血管外 皮质下白质中的纤维蛋白原沉积。除了引起直接白质毒性之外， 纤维蛋白原可以通过整合素B3/表皮生长因子受体（EGFR）损害轴突再生 途径和增加的软骨素硫酸盐蛋白聚糖（CSPG），可以进一步抑制白质修复 通过NGR1途径。我们将评估epigallocatechin-3-gallate（EGCG）给药的影响 PM和CCH暴露后减轻白质损伤。我们希望这可以通过协调 NGR1和67LR结合/内部化和cAMP介导的信号传导的策略。