Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways

脑型疟疾内皮功能障碍机制及屏障恢复途径

基本信息

批准号：
10269051
负责人：
JOSEPH D SMITH
金额：
$ 69.87万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269051
关键词：
3-Dimensional Binding Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Edema Cell model Cerebral Malaria Cerebral hemisphere hemorrhage Clinical Communicable Diseases Complex Complication Disease Drug Targeting Edema Endothelial Cells Endothelium Erythrocytes Failure Falciparum Malaria Functional disorder Goals Human Impairment In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Injury Knowledge MATK gene Malaria Modeling Molecular Mus Obstruction PTK2 gene Parasites Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Plasmodium falciparum Play Property Regression Analysis Regulation Role Sepsis Signal Transduction Stimulus Systems Biology TNF gene Thrombin Thrombosis Time Tissues Variant Viral Hemorrhagic Fevers Work base brain endothelial cell cerebral microvasculature clinical application drug discovery drug repurposing efficacy evaluation endothelial dysfunction in vivo inhibitor/antagonist innovation kinase inhibitor knock-down lentiviral-mediated microbial monolayer mouse model novel therapeutic intervention pathogen repaired small hairpin RNA src-Family Kinases

项目摘要

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.

项目摘要内皮激活，功能障碍和障碍破坏是炎症相关疾病的标志，例如作为疟疾，败血症和病毒出血热。脑疟疾是一种严重的感染并发症恶性疟原虫疟疾寄生虫。在脑疟疾的患者中，红细胞感染了疟疾寄生虫在脑微血管内结合导致微血管阻塞，血栓形成，血脑屏障（BBB）的崩溃和严重的大脑肿胀。如何分子机制复杂的寄生虫和宿主炎症刺激导致血脑屏障的崩溃仅部分是部分理解，恢复BBB诚信的策略仍然有限。激酶抑制剂是潜在的药物高炎性损伤后稳定内皮屏障。这个项目以我们最近的发现为基础特定的激酶抑制剂可促进内皮屏障加强并预防凝血酶诱导的障碍中断。在这个项目中，我们将研究屏障保护激酶作用的机制使用体外人脑内皮细胞模型的抑制剂并研究内皮细胞如何整合信号来自宿主和寄生虫炎症产品。使用新的3D人脑微血管模型，我们还将研究流动干扰如何与内皮激活中的宿主和寄生虫刺激相互作用破坏。最后，我们将通过结合使用的结合来评估屏障保护激酶抑制剂的功效体外3D人脑微血管模型和实验性脑疟疾（ECM）小鼠模型。这拟议的研究将研究内皮屏障完整性的激酶调节，并研究激酶抑制剂稳定内皮屏障特性，其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。