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

Ephrin配体作为脑型疟疾辅助治疗的新靶点

基本信息

批准号：
8771568
负责人：
Tracey Jane Lamb
金额：
$ 24.17万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771568
关键词：
Adherence Adhesions Adhesives Area Binding Blood Platelets Brain C57BL/6 Mouse Cause of Death Cell Adhesion Cell Adhesion Molecules Cerebral Malaria Cerebrum Child Data Deposition Development Disease E-Selectin Endothelial Cells Endothelium Eph Family Receptors Ephrin B Receptor Ephrins Erythrocytes Event Family Genetic Transcription Goals Hospitals Human ICAM1 gene Immune response Infection Inflammation Inflammatory Intercellular adhesion molecule 1 Investments Knowledge Life Ligands Malaria Mediating Mission Modeling Mus Necrosis Outcome P-Selectin Parasites Pharmaceutical Preparations Physiological Plasmodium falciparum Play Property Protein Export Pathway Public Health Receptor Protein-Tyrosine Kinases Research Rodent Role Selectins Stimulus Surface Survival Rate Symptoms System T cell response T-Lymphocyte Testing Tissues Transcript Vaccination Vascular Cell Adhesion Molecule-1 Work base brain tissue design disability human disease improved innovation member novel novel therapeutics prevent public health relevance receptor receptor binding response trafficking volunteer

项目摘要

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.

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% 因 CM 入院的儿童会死亡。在实验性脑疟疾 (ECM) 小鼠中，T 细胞转运至大脑是导致 CM 致死率的核心特征。当孩子入院时 CM 可防止抗疟疾药物治疗后 T 细胞进一步转运至大脑，并防止因 iRBC 坏死而加剧脑部炎症，从而可能提高存活率。 Eph 受体是最大的受体酪氨酸激酶家族。根据序列保守性，它们被分为 2 组——A 家族和 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假定的功能。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，Eph/肝配蛋白分子的“B”家族在 ECM 过程中促进 T 细胞运输至大脑，本提案的目的是确认 EphB 受体/肝配蛋白 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 Ephrin B 配体介导 T 细胞与 EphB 受体的粘附，而微血管中的 EphB 受体上调，以响应 iRBC 的炎症刺激。开展该提案中的工作的基本原理是，传统上参与体内 T 细胞运输的分子，特别是 P-和 E-选择素、ICAM1 和 VCAM1，与粘附的感染疟疾的红细胞 (iRBC) 以及血小板结合在疟疾感染期间被激活，使这些配体无法与 T 细胞结合，这表明大脑中还有其他促进 T 细胞粘附的分子。在我们的初步数据的指导下，这一中心假设将通过追求 3 个具体目标进行检验：1）证明肝配蛋白 B 配体/Eph B 受体在 ECM 中介导 T 细胞运输至大脑中的作用； 2）论证疟疾感染对肝配蛋白介导的T细胞与脑微血管内皮细胞结合的影响； 3) 量化 T 细胞表达的肝配蛋白 B 配体和 Eph B 受体分子在疟疾感染中的粘附特性。该方法具有创新性，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。拟议的研究意义重大，因为目前尚不清楚介导 CM 中 T 细胞运输至大脑的分子，并且确定用于疟疾感染的辅助疗法的新靶点尚待确定。迫切需要。