Endothelial progenitor cells and malaria pathogenesis

内皮祖细胞和疟疾发病机制

• 批准号: 6961033
• 负责人: LINNIE GOLIGHTLY
• 金额: $ 22.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6961033
• 关键词: Africa; Plasmodium falciparum; bone marrow; cell cell interaction; cell migration; child (0-11); clinical research; enzyme linked immunosorbent assay; erythrocytes; flow cytometry; hematopoietic stem cells; host organism interaction; human subject; malaria; microcirculation; nervous system infection; neuropathology; parasite infection mechanism; pathologic process; statistics /biometry; stromal cells; vascular endothelial growth factors; vascular endothelium; virulence

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.

描述（由申请人提供）：疟疾是世界范围内发病率和死亡率的主要原因。大多数死亡是由于感染恶性疟原虫（P. falciparum）寄生虫。脑型疟疾（CM）是这些患者死亡的主要原因。尽管其毒力，恶性疟原虫病和脑型疟疾的病理生理基础知之甚少。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学发现。iRBC与内皮细胞的粘附由其表面上的旋钮介导。这种相互作用导致内皮细胞损伤，如病理学和升高的血浆血管性血友病因子水平（vWF）所示。受损微血管的修复可以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（EPC）的募集来发生。循环EPCs的减少与微血管损伤相关疾病（如心血管疾病）的症状发展相关。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。当循环内皮祖细胞减少并且受损的内皮细胞无法被替换时，就会发生脑型疟疾。本提案的具体目标将检验宿主对微血管损伤的反应是CM发展的原因这一假设。将在加纳南部感染恶性疟原虫的具有不同疾病严重程度（CM、无并发症疟疾和无症状寄生虫血症）的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）探讨恶性疟原虫感染时骨髓对微血管损伤的反应。将通过ELISA测定血浆SDF-1和VEGF水平。所有感染的患者预计都有升高的SDF-1和VEGF水平。