Endothelial progenitor cells and malaria pathogenesis

描述（由申请人提供）：疟疾是全球发病率和死亡率的主要原因。大多数死亡是由于感染了恶性疟原虫（恶性疟原虫）寄生虫。脑型疟疾是这些患者死亡的一个主要原因。尽管其毒性，恶性疟原虫病和脑型疟疾的病理生理基础了解甚少。被感染的红细胞（irbc）在微血管中的隔离是恶性疟原虫感染的主要病理发现。irbc与内皮细胞的粘附是由其表面的旋钮介导的。这种相互作用导致内皮细胞损伤，病理学和血浆血管性血友病因子水平（vWF）升高表明。受损微血管的修复可能通过局部内皮细胞的增殖或迁移或骨髓来源的循环内皮祖细胞（EPCs）的募集来实现。循环EPCs的减少与微血管损伤相关疾病（如心血管疾病）症状的发展有关。我们假设恶性疟原虫感染导致微血管损伤和修复之间的不平衡。当循环EPCs减少，受损的内皮细胞不能被替换时，就会发生脑疟疾。本提案的具体目的将验证宿主对微血管损伤的反应是CM发展的原因。将加纳南部不同疾病严重程度（CM、无并发症疟疾和无症状寄生虫病）的恶性疟原虫感染患者与正常对照进行比较。目的1)确定循环EPCs水平是否与CM的发展相关。循环EPC水平将通过FACS分析确定。预计CM患者的循环EPCs水平较低。目的2)评价恶性疟原虫感染患者骨髓对微血管损伤的反应。ELISA检测血浆SDF-1和VEGF水平。预计所有感染患者的SDF-1和VEGF水平均升高。

DESCRIPTION (provided by applicant): Malaria is a major cause of morbidity and mortality worldwide. The majority of deaths are due to infections with Plasmodium falciparum (P. falciparum) parasites. Cerebral malaria (CM) is a major cause of death in these patients. Despite its virulence, the pathophysiologic basis of P. falciparum disease and cerebral malaria are poorly understood. Sequestration of infected red blood cells (iRBCs) in the microvasculature is a major pathologic finding in P. falciparum infections. iRBCs' adherence to endothelial cells is mediated by knobs on their surface. This interaction results in endothelial cell damage, as indicated by pathology and elevated plasma von Willebrand's factor levels (vWF). Repair of damaged microvasculature may occur either by the proliferation or migration of local endothelial cells or the recruitment of bone marrow derived circulating endothelial progenitor cells (EPCs). The reduction of circulating EPCs has been associated with the development of symptoms in diseases associated with microvascular damage, such as cardiovascular disease. We hypothesize that P. falciparum infection results in an imbalance between microvascular damage and repair. Cerebral malaria occurs when circulating EPCs are diminished and damaged endothelial cells cannot be replaced. The Specific Aims of this proposal will test the hypothesis that the host response to microvascular damage is responsible for the development of CM. P. falciparum infected patients in southern Ghana with different degrees of disease severity (CM, uncomplicated malaria and asymptomatic parasitemia) will be compared with normal controls. Aim 1) To determine if levels of circulating EPCs are associated with the development of CM. Circulating EPC levels will be determined by FACS analysis. Patients with CM are predicted to have low levels of circulating EPCs. Aim 2) To evaluate the bone marrow response to microvascular damage in P. falciparum infections. Plasma SDF-1 and VEGF levels will be determined by ELISA. All infected patients are predicted to have elevated SDF-1 and VEGF levels.