S. MANSONI HOMOLOGUES OF EGF RECEPTOR AND P-GLYCOPROTEIN

血吸虫病是一种慢性、致衰弱的寄生虫病，影响 全球数以亿计的人。这种寄生虫是一种胞外寄生虫 可以存活多年而不会在其体内复制的血吸虫 人类的主人。由于蠕虫必须与它们的宿主密切互动， 正常执行营养吸收和附着等功能 由完整的表膜蛋白执行，寄生虫必须有 开发了避免针对这些蛋白质的免疫攻击的机制。 我们的长期目标是识别这些机制，并试图颠覆 重组表膜免疫效果的研究 蛋白质表位。作为第一步，我们最近克隆了一个全长 编码血吸虫EGF受体同源物(SER)的cDNA和部分 编码哺乳动物血吸虫两种不同同源物的cDNA克隆 多药耐药因子，P-糖蛋白(SMDR1，SMDR2)。而当 研究SER的表达，我们还发现血吸虫使用交替的 剪接途径产生编码羧基的不同SER转录本 终末截断形式的SER，既应该分泌，也应该 膜-锚定。这些变异形式可能会调节免疫反应。 抗SER或结合原本可能存在的抗体而不产生任何后果 对…造成损害 寄生虫。 这项提议的具体目的是广泛地描述正常的 不同SER和SMDR蛋白的表达及免疫原性研究 SER和SMDR的表达将从转录的角度进行研究， 在生命周期中的时间和其转录和本地化 蛋白质产品。完整的本地产品将在 哺乳动物细胞和针对这些蛋白的抗体反应的比较 在感染的小鼠体内也是如此。抗血清和重组抗体 这些蛋白质上的多肽表位将被生成并测试其 识别天然膜蛋白胞外表位的能力 并抑制这些蛋白质的功能。如果结果是 将对它们的疫苗潜力进行有希望的体内测试。 这些研究应该为血吸虫的生物学提供新的见解。 以及两个重要的膜蛋白家族的分子进化。在……里面 此外，它们应为关于以下方面的其他研究提供基础 血清暴露血吸虫表膜蛋白的应用潜力 作为疫苗的靶标。

Schistosomiasis is a chronic, debilitating parasitic disease affecting hundreds of millions of people worldwide. The parasite is an extracellular blood fluke that can survive for many years without replicating in its human host. Since the worms must interact closely with their host, performing functions such as nutrient uptake and attachment normally performed by integral surface membrane proteins, the parasites must have developed mechanisms for avoiding immune attack directed at these proteins. Our long-range goal is to identify these mechanisms and attempt to subvert their effectiveness by immunization with recombinant surface membrane protein epitopes. As a first step, we have recently cloned a full-length cDNA encoding the schistosome homologue of EGF receptor (SER) and partial cDNA clones encoding two distinct schistosome homologues of the mammalian multi-drug resistance factor, P-glycoprotein (SMDR1), SMDR2). While studying SER expression, we also found that schistosomes use alternate splicing pathways to generate variant SER transcripts encoding carboxy- terminally truncated forms of SER that should be both secreted and membrane-anchored. These variant forms may modulate the immune response against SER or bind, without consequence, antibodies that might otherwise be damaging to the parasite. The specific aim of this proposal is to characterize extensively the normal expression and immunogenicity of the different SER and SMDR proteins. Expression of SER and SMDR will be studied in terms of transcription, timing during the life cycle and localization of their transcripts and protein products. Full-length, native products will be expressed within mammalian cells and the antibody response against these proteins compared to that within infected mice. Anti-sera and recombinant antibodies against peptide epitopes on these proteins will be generated and tested for their ability to recognize extracellular epitopes on the native membrane proteins and to inhibit the function of these proteins. If the results are promising, in vivo testing of their vaccine potential will be carried out. These studies should provide new insight into the biology of schistosomes and the molecular evolution of two important membrane protein families. In addition, they should provide the basis for additional studies concerning the potential of using serum-exposed schistosome surface membrane proteins as vaccine targets.