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Brain vascular dysfunction in cerebral malaria

脑型疟疾的脑血管功能障碍

基本信息

批准号：
9017256
负责人：
MARCELO JACOBS-LORENA
金额：
$ 52.54万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2015-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017256
关键词：
Acute Adhesives Astrocytes Autopsy Bacteriophages Binding Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain region Cell Surface Proteins Cerebral Malaria Characteristics Child Coma Complication Conscious Data Delirium Endothelial Cells Endothelium Environment Erythrocyte Membrane Erythrocytes Exhibits Experimental Models Gene Expression Gene Expression Profile Gene Family Genes Heterogeneity High Endothelial Venule Human Immune response In Situ In Vitro Infection Inflammatory Inflammatory Response Intracranial Hypertension Invaded Libraries Ligand Binding Link Liver Malaria Membrane Proteins Military Personnel Modeling Molecular Neurologic Neurologic Dysfunctions Neurons Neuropathogenesis Oligodendroglia Organ Pathogenesis Pathology Pattern Pericytes Physiological Plasmodium Plasmodium falciparum Play Property Protein Binding Relative (related person)Reporting Role Sampling Seizures Signal Transduction Staging Symptoms Testing Vascular Diseases abstracting arteriole brain tissue capillary design gray matter human tissue improved in vitro Model in vivo in vivo Model laser capture microdissection member mortality nervous system disorder novel public health relevance response venule white matter

项目摘要

DESCRIPTION (provided by applicant): CM is a serious complication of Plasmodium falciparum infection, and has a profoundly devastating effect especially on children, non-immune travelers and military personnel. Clinically, CM can result in several neurological problems, which include seizures, reversible coma and is associated with a high mortality of up to 30%, with the highest rate in children. Acute neurological symptoms include impaired consciousness, coma, delirium, seizures, and increased intracranial hypertension. The hallmark of CM pathology is the intra-vascular sequestration of parasitized red blood cells (PRBC) inside high endothelial venules throughout the brain. PRBC bind to the blood brain barrier (BBB) endothelium in both WM and gray matter (GM) but do not invade into the brain. Interestingly, the PRBC sequestration in blood vessels leads to a distinctly different pathology between WM and GM. Recent postmortem studies reveal a clear hemorrhagic pathology within WM. Our previous data showed highly inflammatory responses associated with GM endothelium. Yet, little is known of the factors that cause these differences of the brain endothelium residing in GM versus WM and how any potential differences could relate to divergent responses in CM. Therefore, we hypothesize that, due to differences in the direct physiological environment of GM and WM (e.g. astrocyte-neuronal versus pericyte-oligodendrocytes), the vessel endothelium in these different brain tissues exhibit differing properties. In combination with a specific var-gene expressing Plasmodium binding pattern, these different endothelial properties result in diverging CM pathologies. Here, we propose to study the underlying WM versus GM endothelial differences and responses to PRBC by using in vitro models of human BBB, and compare these differences to in situ human brain samples and vascular responses in an in vivo experimental CM model. This application is response to RFA-HL-15-023 Vascular Dysfunction in the Pathogenesis of Severe Malaria (R01). These studies will provide an improved understanding of the BBB and could provide new understandings of the molecular mechanisms of the brain vessels differentiation in WM versus GM that may also be implicated in other neurological diseases.