White Matter Vessels Incerebral Malaria

白质血管脑疟疾

• 批准号: 8968373
• 负责人: MONIQUE F STINS
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968373
• 关键词: AIDS Dementia Complex; Adhesives; African; Applications Grants; Astrocytes; Autopsy; Binding; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Cerebral Malaria; Characteristics; Child; Coagulation Process; Coma; Complication; Conscious; Data; Development; Discontinuous Capillary; Disease; Dissection; Drug Metabolic Detoxication; Endothelial Cells; Endothelium; Environment; Erythrocyte Membrane; Erythrocytes; Event; Exhibits; Family; Future; Gene Expression; Genes; Goals; Hemorrhage; Heterogeneity; High Endothelial Venule; Human; Immune response; In Situ; In Vitro; Incubated; Infection; Inflammation; Inflammatory Response; Invaded; Knowledge; Lasers; Liver; Malaria; Membrane Proteins; Microarray Analysis; Microbe; Microscopy; Military Personnel; Modeling; Molecular; Nervous System Trauma; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neuropathogenesis; Oligodendroglia; Organ; Pathogenesis; Pathology; Patients; Pattern; Pericytes; Phenotype; Physiological; Plasma Exchange; Plasmodium; Plasmodium falciparum; Property; Reporting; Sampling; Seizures; Signal Transduction; Stimulus; Survivors; Testing; Tight Junctions; Transgenic Mice; Trees; Vascular Endothelium; base; brain tissue; capillary; gray matter; improved; mRNA Differential Displays; member; mortality; nervous system disorder; new therapeutic target; novel; prevent; public health relevance; response; therapeutic target; white matter

 DESCRIPTION (provided by applicant): White matter (WM) abnormalities have been observed in a variety of neurological conditions, including those suffering from cerebral malaria (CM). 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, including impaired consciousness, seizures and reversible coma. CM is associated with a high mortality of up to 30%, with the highest rate in children. In CM survivors, such as African children and non-immune travelers, persistent neurologic deficits may occur. 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 white matter (WM) and gray matter (GM). Interestingly, PRBC do not invade into the brain and their sequestration in blood vessels leads to a distinctly different pathology in the brain's WM versus GM. 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 functional responses in CM. Therefore, we hypothesize that, due to differences in the direct physiological environment of GM and WM (e.g. astrocyte, pericyte- or oligodendrocyte), the vessel endothelium in these different brain tissues exhibit differing functional properties. These differential endothelial properties in combination with specific PRBC binding patterns (due to the expression of alternating var- genes), result in the observed diverging CM pathologies in WM versus GM. In this proposal, we intend to study the differences in functional responses of WM versus GM endothelium to PRBC, using a combination of in vitro BBB models of human brain GM and WM endothelium, and compare these differences to in situ vessels in human brain samples. We will test for selective binding of PRBC and differing host responses with respect to inflammation, barrier response and coagulation markers. For future studies, we will validate our results by analyzing vessels from CM patient samples. This application is an exploratory R21 that combines the analysis and in vitro BBB model for HUMAN CM with analysis of blood vessels derived from human WM and GM brain tissue. 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）：白质（WM）异常已在多种神经系统疾病中观察到，包括患有脑型疟疾（CM）的患者，这是恶性疟原虫感染的严重并发症，尤其具有深远的破坏性影响。对于儿童、无免疫力的旅行者和军事人员，CM 会导致多种神经系统问题，包括意识障碍、癫痫发作和可逆性昏迷，死亡率高达 100%。 30%，在儿童中发生率最高，例如非洲儿童和非免疫旅行者，可能会出现持续性神经功能缺损。 CM 病理学的特点是血管内寄生红细胞 (PRBC) 的隔离。 PRBC 与白质 (WM) 和灰质 (GM) 中的血脑屏障 (BBB) 内皮结合。它们在血管中的隔离导致了 WM 与 GM 中明显不同的病理学，我们之前的数据显示了与 GM 内皮相关的高度炎症反应。 GM 与 WM 中大脑内皮细胞的这些差异以及任何潜在差异如何与 CM 中不同的功能反应相关。因此，我们认为，由于 GM 和 WM 的直接生理环境存在差异。 WM（例如星形胶质细胞、周细胞或少突胶质细胞），这些不同脑组织中的血管内皮表现出不同的功能特性，这些差异的内皮特性与特定的 PRBC 结合模式（由于交替变异基因的表达）相结合，导致了观察 WM 与 GM 中的潜水 CM 病理 在本提案中，我们打算结合使用以下方法来研究 WM 与 GM 内皮对 PRBC 功能反应的差异。人脑 GM 和 WM 内皮细胞的体外 BBB 模型，并将这些差异与人脑样本中的原位血管进行比较，我们将测试 PRBC 的选择性结合以及炎症、屏障反应和凝血标志物方面的不同宿主反应。研究中，我们将通过分析 CM 患者样本的血管来验证我们的结果。该应用程序是一个探索性 R21，它将 HUMAN CM 的分析和体外 BBB 模型与来自人类 WM 和 GM 脑组织的血管分析相结合。研究将加深对 BBB 的理解，并可能为 WM 与 GM 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。