ERYTHROCYTE ENDOTHELIAL INTERACTIONS IN MALARIA

疟疾中红细胞内皮细胞的相互作用

• 批准号: 2061446
• 负责人: Irwin W Sherman
• 金额: $ 15.66万
• 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 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2061446
• 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，估计疟疾引起的人类发病率和死亡率 将近五亿个案件。 其中> 50％是由于一个 物种，恶性疟原虫和> 230万是致命的。 这 疟疾感染的数量增加，全球传播 该疾病是由于抗性寄生虫的出现 廉价的抗疟药氯喹，蚊子的发展 对杀虫剂的耐药性，没有有效疫苗，并且 经济限制。 感染最严重的并发症。 恶性菌是脑疟疾。 在撒哈拉以南非洲不仅仅是 百万儿童死于这种情况。 确切的机制 脑疟疾基础是未知的。 目前，最喜欢的 解释是“机械”假设：血液流过大脑 被寄生的红细胞粘附在后毛细血管后阻碍 静脉内皮通过粘合分子之间的特定相互作用 存在于疟疾感染的表面突起（旋钮）上 红细胞和内皮受体。 粘附也可能涉及 血小板传播，CD36抗原，ICAM-1，降低了可变形性 寄生的红细胞和调节的粘合性特性 内皮细胞。 本研究旨在识别和表征这些研究 疟疾感染红细胞的表面上的分子因子和 负责粘附的内皮细胞，因此， 可以为替代治疗策略提供基础 脑疟疾的治疗。 研究P的粘附素。 恶性菌感染的红细胞，单克隆抗体针对几种 将制备细胞辅助线，并鉴定出表面抗原 通过免疫荧光，免疫沉淀和粘附抑制。 寄生虫编码的粘附素的基因将被克隆，/或粘附素 与红细胞膜蛋白相关的表达。 这 促炎和抗炎药对脐静脉和大脑的影响 内皮细胞（EC）粘附将在体外研究； EC受体 将被识别，并使用类似于该技术来表征 描述了粘附在疟疾感染的红细胞上的粘附素。