Brain vascular dysfunction in cerebral malaria

 描述(申请人提供)：CM是恶性疟原虫感染的严重并发症，对儿童、非免疫力旅行者和军事人员具有深远的破坏性影响。临床上，CM可导致几种神经问题，包括癫痫发作、可逆性昏迷，并与高达30%的死亡率有关，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、神志不清、癫痫发作和颅内压升高。CM病理的特点是大脑内高内皮微静脉内寄生的红细胞(PRBC)在血管内隔离。白质和灰质中的PRBC与血脑屏障(BBB)内皮细胞结合，但不侵入脑内。有趣的是，PRBC在血管中的隔离导致了西医和GM之间截然不同的病理。最近的尸检研究显示，WM内有明显的出血病理。我们先前的数据显示了与GM内皮相关的高度炎症反应。然而，对于导致GM和WM的脑内皮细胞的这些差异的因素以及任何潜在的差异如何与CM的不同反应相关的问题，我们知之甚少。因此，我们推测，由于GM和WM的直接生理环境(如星形胶质细胞-神经元和周细胞-少突胶质细胞)的不同，不同脑组织中的血管内皮细胞表现出不同的特性。与特定的var基因结合 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。在这里，我们建议通过使用人血脑屏障的体外模型来研究WM和GM内皮的潜在差异和对PRBC的反应，并将这些差异与在体实验CM模型中的原位人脑样本和血管反应进行比较。此应用是对RFA-HL-15-023严重疟疾发病机制中的血管功能障碍的响应(R01)。这些研究将提供对血脑屏障的更好的理解，并可能为西医和GM的脑血管分化的分子机制提供新的理解，这些分子机制也可能与其他神经系统疾病有关。

 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.