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

描述(申请人提供)：脑型疟疾(CM)是感染恶性疟原虫的儿童的主要死亡原因。大约20%的患有CM入院的儿童将死亡。在实验性脑疟疾(ECM)小鼠中T细胞向 大脑是导致CM致命性的中心特征。当儿童被送往医院时， 在抗疟疾药物治疗中防止T细胞进一步向大脑转移，并在坏死性iRBC反应中加剧脑部炎症，可能会提高存活率。Eph受体是最大的受体酪氨酸激酶家族。根据序列保守性，它们被分成两组--A和B家族--这些受体分别与肾上腺素A和B配体结合。T细胞同时表达EphB受体和Ephin B配体，推测在T细胞共刺激和运输中起作用。该项目的长期目标是开发一种基于Eph/ePhrin分子家族的CM辅助疗法。我们的初步数据表明，在ECM过程中，“B”家族的EphE/Ephin分子促进了T细胞向大脑的运输，这项提议的目的是确认EphB受体/Ephin B分子在疟疾感染中的这一作用。这一建议的中心假设是T细胞表达Ephin B配体，介导T细胞与微血管中上调的EphB受体的黏附，以响应iRBC的炎症刺激。在这项研究中开展这项工作的基本原理是，传统上参与T细胞在体内运输的分子，特别是P-和E-选择素，ICAM1和VCAM1，与附着的感染疟疾的红细胞(IRBC)以及疟疾感染期间激活的血小板结合，使这些配体无法与T细胞结合，表明还有其他分子促进T细胞在大脑中的黏附。在我们的初步数据的指导下，这一中心假说将通过追求三个具体目标来检验：1)展示在细胞外基质中ePhin B配体/EphB受体在介导T细胞向脑内运输中的作用；2)展示疟疾感染对ePhin介导的T细胞与脑微血管内皮细胞结合的影响；以及3)量化疟疾感染中T细胞表达的ePhin B配体/EphB受体分子的黏附特性。这种方法是创新的，因为EphB受体/Ephin B配体在疟疾感染中的作用尚未被提出。这项拟议的研究具有重要意义，因为在CM中介导T细胞向大脑运输的分子目前尚不清楚，而且用于疟疾感染的辅助治疗的新靶点的识别也是未知的。 急需之物。

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.