Ephrin ligands as novel targets for an adjunct therapy in cerebral malaria

描述（由申请人提供）：脑型疟疾（CM）是感染恶性疟原虫的儿童死亡的主要原因。大约20%的儿童入院与CM将死亡。在实验性脑型疟疾（ECM）小鼠中，T细胞向 脑是导致CM致死性的中心特征。当儿童被送往医院时， CM，防止抗疟疾药物治疗后T细胞进一步运输到大脑，并加剧响应于坏死iRBC的大脑炎症，可以提高存活率。Eph受体是受体酪氨酸激酶的最大家族。基于序列保守性，它们被分为2组-A和B家族-并且这些受体分别结合肝配蛋白A和B配体。T细胞表达EphB受体和肝配蛋白B配体，在T细胞共刺激和运输中具有推定的功能。该项目的长期目标是开发基于Eph /ephrin分子家族的CM辅助治疗。我们的初步数据表明，Eph / ephrin分子的“B”家族在ECM期间促进T细胞向脑的运输，并且该提议的目的是证实Eph B受体/ ephrin B分子在疟疾感染中的这种作用。该提议的中心假设是T细胞表达的肝配蛋白B配体介导T细胞与微脉管系统中上调的Eph B受体的粘附，所述Eph B受体响应于来自iRBC的炎性刺激。开展这项工作的基本原理是，传统上参与身体周围T细胞运输的分子，特别是P-和E-选择素，ICAM 1和VCAM 1，与粘附的疟疾感染的红细胞（iRBC）以及疟疾感染期间激活的血小板结合，这使得这些配体无法与T细胞结合，并表明还有其他分子促进了T细胞在大脑中的粘附。在我们的初步数据的指导下，将通过追求3个具体目标来检验该中心假说：1）证明ephrin B配体/ Eph B受体在介导ECM中T细胞向脑运输中的作用; 2）证明疟疾感染对ephrin介导的T细胞与脑微血管内皮细胞结合的影响;和3）定量疟疾感染中T细胞表达的ephrin B配体和Eph B受体分子的粘附性质。该方法是创新的，因为尚未提出EphB受体/肝配蛋白B配体在疟疾感染中的作用。拟议的研究是重要的，因为介导CM中T细胞运输到大脑的分子目前尚不清楚，并且鉴定用于疟疾感染的辅助疗法的新靶点是未知的。 迫切需要。

DESCRIPTION (provided by applicant): Cerebral malaria (CM) is the leading cause of death in children infected with Plasmodium falciparum. Approximately 20% of children admitted to hospital with CM will die. In the experimental cerebral malaria (ECM) in mice T cell trafficking to the brain is a central feature causing lethality of CM. When children are admitted to hospital with CM, preventing further T cell trafficking to the brain upon anti-malaria drug treatment and exacerbated of cerebral inflammation in response to necrotic iRBCs, may improve survival rates. Eph receptors are the largest family of receptor tyrosine kinases. They have been split into 2 groups based on sequence conservation- the A and B families- and these receptors bind ephrin A and B ligands, respectively. T cells express both EphB receptors and ephrin B ligands, with putative functions in T cell co-stimulation and trafficking. The long-term goal of this projec is to develop an adjunct therapy for CM based on the Eph /ephrin family of molecules. Our preliminary data suggests that the "B" family of Eph / ephrin molecules facilitate T cell traffickig to the brain during ECM and the objective of this proposal is to confirm this role for EphB receptors / ephrin B molecules in malaria infection. The central hypothesis of this proposal is that T cell expressed Ephrin B ligands mediate adhesion of T cells to EphB receptors upregulated in the microvasculature in response to inflammatory stimuli from iRBCs. The rationale for undertaking the work in this proposal is that molecules traditionally involved in T cell trafficking around the body, specifically P- and E- selectins, ICAM1 and VCAM1, bind to adhered malaria-infected red blood cells (iRBCs) as well as platelets activated during malaria infection, making these ligands unavailable for T cell binding and suggesting that there are other molecules that facilitate T cell adhesion in the brain. Guided by our preliminary data, this centra hypothesis will be tested by pursuing 3 specific aims: 1) Demonstrate role of ephrin B ligands / Eph B receptors in mediating T cell trafficking to the brain in ECM; 2) Demonstrate the effect of malaria infection on ephrin-mediated T cell binding to brain microvascular endothelial cells; and 3) Quantify the adhesive properties of T cell-expressed ephrin B ligand and Eph B receptor molecules in malaria infection. The approach is innovative because no role for EphB receptors / ephrin B ligands has yet been proposed in malaria infection. The proposed research is significant because the molecules mediating T cell trafficking to the brain in CM are currently unknown and the identification of new targets for adjunct therapies for use in malaria infection is urgently needed.