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：
9529367
负责人：
MARCELO JACOBS-LORENA
金额：
$ 37.72万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9529367
关键词：
Acute Adhesives Astrocytes Autopsy Bacteriophages Binding Binding Proteins Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain region Cell Surface Proteins Cerebral Malaria Cerebrovascular Disorders Characteristics Child Clinical Coma Complication Conscious Data Delirium Endothelial Cells Endothelium Environment Erythrocyte Membrane Erythrocytes Exhibits Experimental Models Gene Expression Gene Expression Profile Gene Family Genes Hemorrhage Heterogeneity High Endothelial Venule Human Immune response Impairment In Situ In Vitro Infection Inflammatory Inflammatory Response Intracranial Hypertension Libraries Ligand Binding Link Liver Malaria Membrane Proteins Military Personnel Modeling Molecular Neurologic Neurologic Dysfunctions Neurologic Symptoms Neurons Neuropathogenesis Oligodendroglia Organ Parasites Pathogenesis Pathology Pattern Pericytes Physiological Plasmodium Plasmodium falciparum Play Property Reporting Role Sampling Seizures Signal Transduction Testing Vascular Diseases arteriole brain cell brain endothelial cell brain tissue design gray matter human model human tissue improved in vitro Model in vivo 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.

描述（由申请人提供）：CM 是恶性疟原虫感染的严重并发症，尤其对儿童、无免疫力的旅行者和军事人员具有深远的破坏性影响。在临床上，CM 可导致多种神经系统问题，包括癫痫发作、可逆性症状。昏迷，死亡率高达 30%，其中儿童死亡率最高。急性神经系统症状包括意识障碍、昏迷、谵妄、癫痫发作和增加。颅内高压。 CM 病理学的标志是整个大脑的高内皮微静脉内寄生红细胞 (PRBC) 与 WM 和灰质中的血脑屏障 (BBB) 内皮结合。 GM）但不侵入大脑，这表明 PRBC 隔离在血管中导致 WM 和 GM 之间明显不同的病理学。我们之前的数据显示与 GM 内皮细胞相关的高度炎症反应，然而，对于导致 GM 与 WM 脑内皮细胞差异的因素以及任何潜在差异如何与 CM 中的不同反应相关，我们知之甚少。因此，我们认为，由于 GM 和 WM 直接生理环境的差异（例如星形胶质细胞-神经元与周细胞-少突胶质细胞），这些不同的血管内皮细胞脑组织与特定的 var 基因结合表现出不同的特性。表达疟原虫结合模式，这些不同的内皮特性导致不同的 CM 病理学在这里，我们建议通过使用人类 BBB 的体外模型来研究潜在的 WM 与 GM 内皮差异以及对 PRBC 的反应，并将这些差异与原位人脑进行比较。体内实验 CM 模型中的样本和血管反应该应用是针对严重疟疾发病机制中的 RFA-HL-15-023 血管功能障碍的反应。 (R01).这些研究将加深对 BBB 的理解，并可能为 WM 与 GM 中脑血管分化的分子机制提供新的理解，这也可能与其他神经系统疾病有关。