Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways

项目摘要 内皮激活、功能障碍和屏障破坏是炎症相关疾病的特征，如 疟疾、败血症和病毒性出血热。脑型疟疾是感染脑型疟疾的严重并发症 恶性疟原虫疟疾寄生虫。在脑型疟疾患者中，红细胞感染 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。分子机制是如何使 复杂的寄生虫和宿主炎症刺激导致血脑屏障的破坏只是部分的 理解，恢复血脑屏障完整性的战略仍然有限。激酶抑制剂是一种潜在的药物 在高炎症损伤后稳定内皮细胞屏障。这个项目是以我们最近的发现为基础的。 特异性激酶抑制剂促进内皮屏障增强和对抗凝血酶诱导的损伤 障碍物破坏。在本项目中，我们将研究屏障保护性激酶的作用机制(S)。 使用体外人脑内皮细胞模型和研究内皮细胞如何整合信号的抑制剂 来自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 颠覆。最后，我们将评估屏障保护性激酶抑制剂的有效性 体外三维人脑微血管模型和实验性脑疟疾(ECM)小鼠模型。这个 拟议的研究将研究激酶对内皮屏障完整性的调节，并探讨 用于稳定内皮屏障特性的激酶抑制剂，长期目标是开发新的 治疗与内皮功能障碍相关的多种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.