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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：
10466868
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/10466868
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 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