ERYTHROCYTE ENDOTHELIAL INTERACTIONS IN MALARIA

疟疾中红细胞内皮细胞的相互作用

• 批准号: 2327150
• 负责人: Irwin W Sherman
• 金额: $ 17.34万
• 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/2327150
• 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5亿个病例。其中50%的原因是 恶性疟原虫和~gt；230万是致命的。这个 疟疾感染人数的增加，以及疟疾在全球的传播 这种疾病是由于出现了对该病毒具有抗药性的寄生虫 廉价的抗疟疾药物氯喹，蚊子的开发 对杀虫剂的抗药性，缺乏有效的疫苗，以及 经济上的限制。最严重的感染并发症是P. 恶性疟是一种脑型疟疾。在撒哈拉以南非洲地区， 数以百万计的儿童死于这种疾病。精确的机制， 脑型疟疾的潜在原因是未知的。目前，最受欢迎的 解释是“机械”假说：血液流经大脑 被寄生的红细胞附着在毛细血管后部而受阻 黏附分子与小静脉内皮细胞的特异性相互作用 在疟疾感染者的表面突起(旋钮)上 红细胞和血管内皮细胞受体。粘连还可能涉及到 凝血酶敏感蛋白、CD36抗原、ICAM-1降低血管变形性 被寄生的红细胞，以及对粘附性的调节 内皮细胞。 本研究的目的是确定和描述这些 感染疟疾的红细胞表面的分子因子和 负责黏附的内皮细胞，因此， 可为其他治疗策略提供基础。 治疗脑型疟疾。目的：研究粘附素的性质。 感染恶性疟原虫的红细胞，抗几种 将制备细胞贴壁株，并鉴定表面抗原 通过免疫荧光、免疫沉淀和抑制黏附。 寄生虫编码的粘附素的基因将被克隆，和/或粘附素 与红细胞膜蛋白相关的表达测定。这个 促炎药和抗炎药对脐静脉和脑的影响 将在体外研究内皮细胞(EC)的黏附；EC受体 将被识别，并使用类似于 被描述为感染疟疾的红细胞上的粘附素。