Cerebral malaria is a deadly complication of malaria infection associated with the accumulation of P. falciparum infected erythrocytes (IEs) in cerebral microvasculature, but the molecular mechanisms of pathogenesis are still poorly understood. IE binding is primarily mediated by a large family of proteins, called the var genes or P. falciparum erythrocyte membrane protein 1 (PfEMP1). Our group and others recently discovered that specific PfEMP1 proteins, termed DC8 and DC13, encode cerebral binding activity and are associated with cerebral malaria infections in children. In this project, we will characterize the host binding partners that mediate DC8-infected erythrocyte adhesion to brain endothelial cells and characterize signaling pathways that may be initiated by P. falciparum cytoadhesion. We will further investigate if DC8 and DC13 are the principal var products that mediate high affinity binding to brain endothelial cells and define critical interaction residues tat mediate parasite adhesion to a novel brain receptor adhesion candidate. These studies will contribute to a detailed characterization of the molecular mechanisms associated with P. falciparum-IE sequestration in brain and define endothelial signaling pathways that may contribute to cerebral malaria pathogenesis.