Beta-catenin signaling in endothelial cells during cerebral malaria

脑型疟疾期间内皮细胞中的β-连环蛋白信号传导

基本信息

批准号：
9144854
负责人：
Edward A Fisher
金额：
$ 48.39万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144854
关键词：
AGTR2 gene Angiotensin II Receptor Angiotensin Receptor Antimalarials Blood Blood - brain barrier anatomy Brain Cause of Death Cell Nucleus Cells Cerebral Malaria Cessation of life Characteristics Clinical Trials Complication Development Disease Endothelial Cells Endothelium Erythrocytes Evaluation Event Genetic Transcription Goals Health Hemorrhage Human Impaired cognition In Vitro Intercellular Junctions Intercellular adhesion molecule 1 Losartan Malaria Mediating Microcirculation Mus Neurologic Parasites Pathology Pathway interactions Patients Pharmaceutical Preparations Plasmodium Plasmodium falciparum Proteins Receptor Signaling Role Signal Pathway Signal Transduction Signaling Molecule Surface Symptoms Therapy trial Virulent abstracting activated protein C receptor beta catenin brain endothelial cell brain tissue human disease in vitro Model killings monolayer mouse model receptor therapy development

项目摘要

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.

描述（由适用提供）：脑疟疾（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。虽然可用的抗疟疾药物可有效清除血液中的寄生虫，但它们却不对脑疟疾具有特定的作用。使用体外模型，我们发现恶性疟原虫-IRBC在人脑微血管内皮细胞（HBMEC）中诱导β-catenin的激活，从而导致它们与底物脱离并破坏内端细胞间接头。 β-catenin的激活诱导HBMEC核中TCF/LEF的转录，这介导了恶性疟原虫-IRBC诱导的破坏。我们观察到抑制β-catenin激活的治疗导致对P的保护。恶性菌在体外和针对小鼠实验CM的内皮细胞单层造成的损伤。我们建议，脑内皮中的β-catenin激活是CM病理发展中的一个核心事件，可以探索其抑制作用，以探索针对脑疟疾的辅助治疗。我们已经确定，血管紧张素II受体诱导的信号传导（AT1和AT2）调节内皮细胞中的β-catenin，因此，内皮间结和血脑屏障的完整性的完整性。这些受体的调节剂，其中一些已经被批准或用于人类使用的临床试验，即使在出现严重的神经系统症状后开始治疗，也可以保护小鼠免受实验CM的影响。我们打算在内皮细胞中鉴定恶性疟原虫诱导的信号通路，从而导致β-链氨酸蛋白蛋白的激活及其抑制AT2信号级联的抑制，以评估这些途径在人类疾病中的重要性。在体外，使用人脑微血管内皮细胞的三个沟通方法，用于大脑疟疾患者的脑疟疾和内皮细胞的小鼠模型，我们打算确定这些信号传导途径在人类脑疟疾中的作用。我们的主要目标是了解恶性疟原虫诱导的内皮细胞中的信号传导，从而导致脑疟疾期间血液脑屏障的破坏，以开发疗法，通过抑制这些信号传导途径，这些疗法将特别预防脑疟疾病理学。这些发现可能与其他脑出血性疾病的治疗有关，因为更牢固的内皮交界将导致更强的血脑屏障，从而限制出血性病理。