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Endothelial Cell Uptake of Infected Erythrocytes in Cerebral Malaria

脑型疟疾中感染红细胞的内皮细胞摄取

基本信息

批准号：
9112857
负责人：
Keith Burridge
金额：
$ 22.48万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9112857
关键词：
Affect Antimalarials Apical Apoptosis Binding Blood - brain barrier anatomy Blood Vessels Brain CD36 gene Carrier Proteins Cell Communication Cell Death Cell Line Cell membrane Cerebral Malaria Cerebrovascular system Cerebrum Clinical Coma Communicable Diseases Disease Endothelial Cells Endothelium Erythrocytes Event Functional disorder Future Goals Grant Health Human ICAM1 gene Image Analysis In Vitro Infection Inflammation Inflammatory Response Intercellular Junctions Lead Leukocytes Link Malaria Mediating Membrane Proteins Modification Molecular Necrosis Neurologic Obstruction Oxygen Parasitemia Parasites Pathogenesis Pathology Pathway interactions Peripheral Permeability Plasmodium falciparum Play Reporting Role Signal Pathway Signal Transduction Staging Symptoms TNF gene Testing Tight Junctions Tissues Up-Regulation Work activated protein C receptor brain endothelial cell burden of illness improved killings malaria infection migration monolayer mortality novel peripheral blood vessel prevent receptor survival outcome therapeutic development uptake

项目摘要

DESCRIPTION (provided by applicant): Malaria due to Plasmodium falciparum remains one of the largest global infectious disease burdens, infecting over 200 million and killing nearly 700,000 people annually. Of several possible disease manifestations, cerebral malaria has the worst survival outcomes. Cerebral malaria, characterized by coma and neurological deficits, ensues when parasitized red blood cells (pRBCs) sequester in the cerebral vasculature. Cytoadherence can contribute to disease by obstructing peripheral blood vessels, limiting oxygen delivery to tissue, and inducing significant inflammation. Cerebral pRBC sequestration is linked to breakdown of the blood brain barrier, yet the molecular mechanisms mediating vascular damage in cerebral malaria are poorly understood. The host inflammatory response plays a major role, but a more complete understanding of sequestration-related pathophysiology is necessary to develop adjunct therapies for cerebral malaria. Recent in vitro findings demonstrate that human brain endothelial cells (ECs) take up pRBCs via formation of an apical cup resembling endothelial protrusions known to mediate leukocyte transendothelial migration (TEM). ICAM1 binding in TEM activates signaling that induces cytoskeletal remodeling and junction opening to allow for migration either through or between ECs. Since pRBCs also bind ICAM1 and the cup- formation described in pRBC uptake resembles that associated with transcellular TEM, we hypothesize that pRBC cytoadherence can mistakenly induce uptake via TEM pathways and that this contributes to the pathology of cerebral malaria. Our aims seek: 1) to explore the relationship between cup formation and pRBC uptake by ECs, investigating the receptors involved and comparing different clinical isolates of P. falciparum for their ability to induce cup formation; and 2) to determine how pRBC-induced cups and uptake contribute to disruption of the EC barrier, whether this occurs by signaling pathways that open junctions or by inducing cell death. Our long term goal is to understand how pRBCs induce endothelial activation and blood brain barrier breakdown in order to improve therapeutic development. Not only is characterizing endothelial pRBC uptake in the context of leukocyte TEM pathways a novel idea, but exploring pRBC uptake has significant implications for understanding and controlling cerebral malaria pathology.