Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways

项目摘要 内皮活化、功能障碍和屏障破坏是炎症相关疾病的标志，如炎症性疾病、炎症性疾病和炎症性疾病。 疟疾败血症病毒性出血热脑型疟疾是一种严重的并发症， 恶性疟原虫疟疾寄生虫在脑型疟疾患者中， 疟疾寄生虫结合在脑微血管内，导致微血管阻塞，血栓形成， 血脑屏障（BBB）的破坏和严重的脑肿胀。分子机制如何 引起血脑屏障破坏的复杂寄生虫和宿主炎症刺激物仅部分地 然而，恢复BBB完整性的策略仍然有限。激酶抑制剂是潜在的药物， 稳定炎症损伤后的内皮屏障。这个项目建立在我们最近的发现之上 特异性激酶抑制剂促进内皮屏障强化并保护免于凝血酶诱导的内皮细胞损伤。 屏障破坏在这个项目中，我们将研究屏障保护激酶的作用机制 抑制剂使用体外人脑内皮细胞模型和研究如何内皮细胞整合信号 宿主和寄生虫的炎症产物使用新的3D人脑微血管模型，我们还将 研究血流紊乱如何与宿主和寄生虫刺激在内皮激活和屏障中相互作用 破坏最后，我们将评估屏障保护性激酶抑制剂的疗效， 体外三维人脑微血管模型和实验性脑型疟疾（ECM）小鼠模型。的 拟议的研究将研究激酶对内皮屏障完整性的调节， 激酶抑制剂，以稳定内皮屏障性能，长期目标是开发新的 用于治疗与内皮功能障碍相关的广泛临床疾病的治疗方法。

Project Abstract Endothelial activation, dysfunction, and barrier disruption are hallmarks of inflammation-related diseases, such as malaria, sepsis, and viral hemorrhagic fever. Cerebral malaria is a severe complication of infection with Plasmodium falciparum malaria parasites. In patients with cerebral malaria, red blood cells infected with malaria parasites bind within cerebral microvessels leading to microvascular obstruction, thrombosis, breakdown of the blood-brain barrier (BBB), and severe brain swelling. The molecular mechanisms of how the complex parasite and host inflammatory stimuli cause breakdown of the blood-brain barrier are only partially understood, and strategies to restore BBB integrity remain limited. Kinase inhibitors are potential drugs to stabilize the endothelial barrier following hyperinflammatory damage. This project builds on our recent findings that specific kinase inhibitors promote endothelial barrier strengthening and protect against thrombin-induced barrier disruption. In this project, we will investigate the mechanism(s) of action of barrier-protective kinase inhibitors using in vitro human brain endothelial cell models and study how endothelial cells integrate signals from host and parasite inflammatory products. Using a new 3D human brain microvessel model, we will also study how flow disturbances interact with host and parasite stimuli in endothelial activation and barrier disruption. Finally, we will evaluate the efficacy of barrier-protective kinase inhibitors using a combination of the in vitro 3D human brain microvessel model and an experimental cerebral malaria (ECM) mouse model. The proposed studies will study kinase regulation of endothelial barrier integrity and investigate the potential of kinase inhibitors to stabilize endothelial barrier properties, with the long-term goal of developing new therapeutic approaches to treat a wide spectrum of clinical disease associated with endothelial dysfunction.