Beta-catenin signaling in endothelial cells during cerebral malaria

 描述(申请人提供)：脑型疟疾(CM)是由恶性疟原虫感染的红细胞(IRBC)与宿主脑内皮细胞相互作用引起的。虽然现有的抗疟疾药物可以有效地清除血液中的寄生虫，但它们不能。 对脑型疟疾有特效。利用体外模型，我们发现恶性疟原虫-红细胞可诱导人脑微血管内皮细胞β-连环蛋白的激活，导致其脱离底物并破坏内皮细胞间的连接。β-catenin的激活可诱导HbMEC核内Tcf/Lef的转录，从而介导恶性疟原虫-irbc的破坏作用。我们观察到，抑制β-连环蛋白激活的治疗，导致了对P. 恶性疟原虫致小鼠内皮细胞单层损伤及抗实验性CM。我们认为，脑内皮细胞β-连环蛋白的激活是CM病理发展的中心事件，其抑制作用可用于辅助治疗脑型疟疾。我们已经发现血管紧张素II受体(AT1和AT2)诱导的信号调节内皮细胞的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。这些受体的调节剂中的一些已经被批准或正在进行临床试验，用于人类，即使在出现严重的神经症状后开始治疗时，也能保护小鼠免受实验性CM的影响。我们打算确定恶性疟原虫在内皮细胞中诱导的导致β-连环蛋白激活的信号通路以及AT2信号级联通路的抑制作用，以评估这些通路在人类疾病中的重要性。利用体外培养的人脑微血管内皮细胞、小鼠脑疟疾模型和脑疟疾患者内皮细胞的三管齐下的方法，我们打算确定这些信号通路在人脑疟疾中的作用。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通路来专门预防脑型疟疾病理的治疗方法。这些发现可能与其他脑出血疾病的治疗有关，因为更强大的内皮细胞间连接将导致更强大的血脑屏障，从而限制出血病理。

 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.