CYTOADHERENCE IN MATERNAL MALARIA

母体疟疾中的细胞粘附

• 批准号: 6869330
• 负责人: CHANNE D GOWDA
• 金额: $ 19.49万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869330
• 关键词: Plasmodium falciparum; affinity chromatography; affinity labeling; antibody formation; antibody specificity; blood chemistry; cell adhesion; cellular immunity; cellular pathology; chondroitin sulfates; clinical research; electrospray ionization mass spectrometry; enzyme linked immunosorbent assay; erythrocytes; human tissue; laboratory mouse; laboratory rabbit; malaria; malaria vaccines; microarray technology; placenta; polymerase chain reaction; receptor binding; receptor expression; small interfering RNA; western blottings

DESCRIPTION (provided by the applicant): In pregnant women, red blood cells infected with Plasmodium falciparum (IRBCs) selectively adhere in the pregnant women, placenta, causing several clinical manifestations including low birth weight, stillbirth, abortion of the fetus, and anemia and death in the mother. A number of studies have shown that the placental IRBC adherence is mediated by chondroitin 4-sulfate (C4S). During the previous grant period, it was established that a uniquely low sulfated chondroitin sulfate proteoglycan (CSPG) is the natural receptor for IRBC adherence in the placenta. Several critical structural elements of C4S involved in the process were determined. In contrast to the level of information available on the C4S structural interactions, very little is known about the parasite adhesive protein on the IRBC surface. Another aspect of the placental IRBC adherence that is not fully understood is the possible role of additional receptors. Recently, hyaluronic acid and fetal Fc receptor have been implicated, but their roles remain unclear. The long-term objective of this investigation is to delineate the structural interactions involved in the placental IRBC adherence, and use this knowledge to develop therapeutics and/or a vaccine for placental malaria. To accomplish this goal, the parasite adhesive protein has to be unequivocally identified and its adhesive domain determined. Therefore, the aims of this proposal are to investigate three important aspects that represent logical extensions of the studies during the previous granting period. (1) Determine fully the C4S structural elements involved in IRBC adhesion. Prepare photo-affinity probe using the structurally defined C4S dodecasaccharide. Isolate the parasite adhesive protein by photo-affinity tagging and by C4S-affinity chromatography and characterize biochemically. (2) Identify and characterize the parasite protein(s) by functional genomic approaches, and by C4S-IRBC adhesion inhibition analysis using antibodies against identified proteins. (3) Determine whether hyaluronic acid and fetal Fc receptor also mediate placental IRBC adhesion by testing blood samples from a large number of P. falciparum-infected placentas.

描述（由申请人提供）：在孕妇中，感染了恶性疟原虫（IRBC）的红细胞在孕妇中有选择地粘附，胎盘，造成多种临床表现，包括低出生体重，胎儿堕胎，胎儿流产以及母亲的贫血和死亡。许多研究表明，胎盘IRBC依从性是由软骨素4-硫酸盐（C4S）介导的。在上一个赠款期间，确定独特的低硫酸软骨素硫酸软骨蛋白聚糖（CSPG）是胎盘中IRBC依从性的自然受体。确定了参与该过程的C4的几个关键结构元素。与C4S结构相互作用的信息水平相反，关于IRBC表面上的寄生虫粘合剂蛋白知之甚少。胎盘IRBC依从性的另一个方面尚未完全理解，是其他受体的可能作用。最近，透明质酸和胎儿FC受体已涉及，但它们的作用尚不清楚。这项调查的长期目标是描述胎盘IRBC依从性涉及的结构相互作用，并利用这些知识来开发治疗疗法和/或疫苗作为胎盘疟疾。为了实现这一目标，必须明确鉴定寄生虫粘合剂蛋白并确定其粘合剂结构域。因此，该提案的目的是调查代表上一个授予期间研究逻辑扩展的三个重要方面。 （1）完全确定与IRBC粘附有关的C4S结构元件。使用结构定义的C4S DEDECASACACAIDE准备照片亲和力探针。通过光亲和力标记和C4s亲密色谱分离寄生虫粘合剂蛋白，并以生化为特征。 （2）使用功能基因组方法以及使用针对鉴定蛋白的抗体来识别和表征寄生虫蛋白，并通过C4S-IRBC粘附抑制分析。 （3）确定透明质酸和胎儿FC受体是否还通过测试来自大量恶性疟原虫感染的胎盘的血液样本来介导胎盘IRBC粘附。