ERYTHROCYTE-ENDOTHELIAL INTERACTIONS IN MALARIA

疟疾中红细胞-内皮细胞的相互作用

• 批准号: 3131192
• 负责人: Irwin W Sherman
• 金额: $ 14.94万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3131192
• 关键词: Plasmodium falciparum; SDS polyacrylamide gel electrophoresis; affinity chromatography; antiinflammatory agents; brain; cell adhesion; cell cell interaction; diagnosis design /evaluation; erythrocytes; gel electrophoresis; genetic manipulation; human subject; immunofluorescence technique; immunoprecipitation; laboratory mouse; laboratory rabbit; malaria; medical complication; molecular cloning; molecular pathology; monoclonal antibody; nervous system infection; nucleic acid hybridization; parasitic disease chemotherapy; protozoal antigen; surface antigens; tissue /cell culture; vascular endothelium

In 1986, the human morbidity and mortality due to malaria was estimated to be nearly a half-billion cases. Of these > 50% were due to one species, Plasmodium falciparum, and > 2.3 million were fatal. The increase in numbers of malaria infections, and the worldwide spread of the disease, is due to the appearance of parasites resistant to the Inexpensive antimalarial drug chloroquine, the development of mosquito resistance to insecticides, the absence of an effective vaccine, and economic constraints. The most severe complication of Infections with P. falciparum is cerebral malaria. In sub-Saharan Africa more than a million children die of this condition. The precise mechanisms that underlie cerebral malaria are unknown. Currently, the most favored explanation is the "mechanical" hypothesis: blood flow through the brain is impeded by the adherence of parasitized red cells to the postcapillary venular endothelium by a specific interaction between adhesive molecules present on surface protuberances (knobs) of the malaria-infected erythrocyte and an endothelial receptor. Adhesion may also involve thrombospondin, CD36 antigen, ICAM-1, decreased deformability of the parasitized red cell, and modulation of the adhesive properties of the endothelial cell. The present study is designed to identify and characterize those molecular factors on the surfaces of the malaria-infected erythrocyte and the endothelial cell that are responsible for adhesion, and as such, could provide a basis for alternative therapeutic strategies for the treatment of cerebral malaria. To study the adhesin of the P. falciparum-infected red cell, monoclonal antibodies against several cytoadherent lines will be prepared, and the surface antigen identified by immunofluorescence, immunoprecipitation, and inhibition of adhesion. The gene for the parasite-encoded adhesin will be cloned, and/or adhesin expression associated with red cell membrane proteins determined. The effect of pro- and anti-inflammatory agents on umbilical vein and brain endothelial cell (EC) adhesion will be studied in vitro; the EC receptor will be identified, and characterized using techniques similar to those described for the adhesins on the malaria-infected red cell.

1986年，估计了疟疾造成的人类发病率和死亡率， 将近5亿例。 其中，50%以上是由于 种，恶性疟原虫，和> 230万是致命的。 的 疟疾感染人数增加，以及疟疾在全世界蔓延， 这种疾病是由于寄生虫的出现抵抗 廉价的抗疟药氯喹，蚊子的发展 对杀虫剂的抗药性，缺乏有效的疫苗， 经济限制。 感染P. 恶性疟原虫是脑型疟疾。 在撒哈拉以南非洲， 数百万儿童死于这种疾病。 的精确机制 脑型疟疾的病因尚不清楚 目前，最受欢迎的 一种解释是“机械”假说：血液流经大脑 被寄生的红细胞粘附在毛细血管后 粘附分子之间的特异性相互作用 存在于疟疾感染者的表面突起（旋钮）上， 红细胞和内皮受体。 粘附还可能涉及 血小板反应蛋白、CD 36抗原、ICAM-1，降低了 寄生红细胞的粘附特性的调节， 内皮细胞 本研究旨在识别和表征这些 感染疟疾的红细胞表面的分子因子， 负责粘附的内皮细胞，因此， 可以为替代治疗策略提供基础， 治疗脑型疟疾。 为了研究P. 恶性疟原虫感染的红细胞，抗几种 将制备细胞粘附细胞系，并鉴定表面抗原 通过免疫荧光、免疫沉淀和粘附抑制。 将克隆寄生虫编码的粘附素的基因，和/或粘附素 测定与红细胞膜蛋白相关的表达。 的 促炎剂和抗炎剂对脐静脉和脑影响 将在体外研究内皮细胞（EC）粘附; EC受体 将被识别，并使用类似的技术， 描述了疟疾感染红细胞上的粘附素。