Beta-catenin signaling in endothelial cells during cerebral malaria

 描述（由申请人提供）：脑型疟疾（CM）是由恶性疟原虫感染的红细胞（iRBC）和宿主脑内皮细胞之间的相互作用引起的。虽然现有的抗疟疾药物在清除血液中的寄生虫方面是有效的， 对脑型疟疾有特效使用体外模型，我们发现恶性疟原虫-iRBC诱导人脑微血管内皮细胞（HBMEC）中β-连环蛋白的活化，这导致它们从基底上脱离并破坏内皮细胞间连接。β-catenin的激活诱导HBMEC核中Tcf/LEF的转录，其介导恶性疟原虫-iRBC诱导的破坏。我们观察到，抑制β-连环蛋白活化的治疗导致对P. 恶性疟原虫诱导的体外内皮细胞单层损伤和小鼠实验CM。我们认为脑内皮细胞中β-连环蛋白的激活是CM病理学发展的中心事件，并且可以探索其抑制以辅助治疗脑型疟疾。我们已经确定，血管紧张素II受体（AT 1和AT 2）诱导的信号传导调节内皮细胞中的β-连环蛋白，从而调节内皮细胞间连接的完整性和血脑屏障的完整性。这些受体的调节剂，其中一些已经被批准或在临床试验中用于人类，保护小鼠免受实验性CM，即使在严重的神经症状出现后开始治疗。我们打算鉴定恶性疟原虫诱导的内皮细胞中导致β- catenin活化的信号通路及其通过AT 2信号级联的抑制，以评估这些通路在人类疾病中的重要性。使用三管齐下的方法与人脑微血管内皮细胞在体外，脑型疟疾的小鼠模型和脑型疟疾患者的内皮细胞，我们打算确定这些信号通路在人脑型疟疾中的作用。我们的主要目标是了解恶性疟原虫诱导的内皮细胞信号传导，导致脑型疟疾期间血脑屏障的破坏，以开发通过抑制这些信号传导途径，将特异性保护脑型疟疾病理的疗法。这些发现可能与其他脑出血性疾病的治疗相关，因为更稳健的内皮间连接将导致更强的血脑屏障，这将限制出血性病理学。

 DESCRIPTION (provided by applicant): Cerebral malaria (CM) is caused by the interaction between Plasmodium falciparum infected erythrocytes (iRBC) and host brain endothelial cells. While available anti-malarial drugs are effective at clearing parasites from the blood, they do not have specific effects against cerebral malaria. Using an in vitro model, we have found that P. falciparum-iRBC induce the activation of β-catenin in human brain microvascular endothelial cells (HBMEC), which results in their detachment from the substrate and disruption of inter-endothelial cell junctions. The activation of β-catenin induces transcription of Tcf/LEF in the nucleus of HBMEC, which mediates the disruptions induced by P. falciparum-iRBC. We observed that treatments that inhibit the activation of β-catenin, result in protection against P. falciparum-induced damage in endothelial cell monolayers in vitro and against experimental CM in mice. We propose that β-catenin activation in brain endothelium is a central event in the development of CM pathology and that its inhibition can be explored for adjunct treatment against cerebral malaria. We have identified that the signaling induced by angiotensin II receptors (AT1 and AT2) modulates β-catenin in endothelial cells and, as a result, the integrity of the inter-endothelial junctions and blood brain barrier integrity. Modulators of these receptors some of which are already approved or in clinical trials for use in humans, protect mice from experimental CM even when treatment is started after severe neurological symptoms are present. We intend to identify the P. falciparum-induced signaling pathway in endothelial cells leading to activation of β- catenin and its inhibition by the AT2 signaling cascade to evaluate th importance of these pathways in human disease. Using a three-pronged approach with human brain microvascular endothelial cells in vitro, mouse models for cerebral malaria and endothelial cells from cerebral malaria patients, we intend to determine the role of these signaling pathways in human cerebral malaria. Our main goal is to understand P. falciparum- induced signaling in endothelial cells leading to the disruption of the blood brain barrier during cerebral malaria to develop therapies that, by inhibiting these signaling pathways, will specifically protect against cerebral malaria pathology. These findings may be relevant to the treatment of other brain hemorrhagic diseases, since more robust inter- endothelial junctions will result in a stronger blood brain barrier that would limit hemorrhagic pathology.