Cationic CAMKIIN nanoparticles that reduce chlorine-induced airway oxidative stress

项目摘要 氯是一种对人体有害的化学物质。急性吸入高浓度氯 导致呼吸道上皮细胞死亡，并对呼吸健康造成不利影响， 包括呼吸道重塑和高反应性。在小鼠氯气暴露模型中，动物 在大气道处出现炎症和纤维化。这种炎症和纤维化已经 据报道与线粒体损伤和氧化应激的产生有关， 活性氧物种。我们的研究小组已经证明了钙/钙调蛋白依赖的蛋白激酶 II(CaMKII)在呼吸道ROS的产生中起着关键作用。在本提案中，我们将测试 假设，作为对氯气攻击的反应，CaMKII有助于诱导 呼吸道炎症的标志性特征。利用一种新的药物输送系统，我们将揭露 小鼠对包裹在PLGA纳米粒中的CaMKII抑制肽(CaMKIIN)。这些NPs将是 通过口咽滴注直接输送到肺部。此外，我们将包括一种壳聚糖 包被CaMKIin的PLGA-NPs以增加肺细胞的摄取，从而减少 氧化应激和纤维化。该项目将通过首先评估CaMKII激活完成 和幼年小鼠肺组织中ROS的表达水平 确定CaMKII抑制剂负载的阳离子纳米颗粒是否可以减轻ROS的表达和 氯气暴露后的肺损伤。

Project Summary Chlorine is a chemical agent that is harmful to humans. Acute inhalation of high levels of chlorine results in the death of airway epithelial cells and leads to adverse effects on respiratory health, including airway remodeling and hyperreactivity. In a mouse chlorine exposure model, animals developed inflammation and fibrosis in large airways. This inflammation and fibrosis has been reported to be linked to damage to mitochondria and the generation of oxidative stress and reactive oxygen species. Our group has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in ROS generation in the airways. In this proposal, we will test the hypothesis that, in response to chlorine gas challenge, CaMKII contributes to the induction of hallmark features of airway inflammation. Utilizing a novel drug delivery system, we will expose mice to a CaMKII inhibitor peptide (CaMKIIN) encapsulated in PLGA NPs. These NPs will be directly delivered to the lung via oropharyngeal instillation. Furthermore, we will include a chitosan coating of the CaMKIIN-loaded PLGA-NPs to increase uptake in lung cells thereby reducing oxidative stress and fibrosis. This project will be completed by first evaluating CaMKII activation and ROS expression levels in the lungs of juvenile mice following chlorine exposure and then determining if a CaMKII inhibitor-loaded cationic nanoparticle can mitigate ROS expression and lung damage following chlorine exposure.