S. MANSONI HOMOLOGUES OF EGF RECEPTOR AND P-GLYCOPROTEIN

血吸虫病是一种慢性、使人衰弱的寄生虫病， 全世界数以亿计的人。 寄生虫是一种细胞外 血吸虫，可以生存多年，而不复制在其 人类宿主 由于蠕虫必须与宿主密切互动， 正常执行诸如营养吸收和附着的功能 由完整的表面膜蛋白执行，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。 我们的长期目标是确定这些机制，并试图颠覆 通过用重组表面膜免疫它们的有效性 蛋白质表位 作为第一步，我们最近克隆了一个全长的 编码EGF受体（SER）的同源体的cDNA和部分 编码两种不同的哺乳动物染色体同源物的cDNA克隆 多药耐药因子，P-糖蛋白（SMDR 1），SMDR 2）。 而 研究SER表达，我们还发现， 剪接途径以产生编码羧基- SER的末端截短形式，其应该是分泌的， 膜锚定。 这些变异形式可以调节免疫反应 或结合，而没有后果，抗体，否则可能 会损伤 寄生虫 这项建议的具体目的是广泛地描述正常的 不同SER和SMDR蛋白的表达和免疫原性。 SER和SMDR的表达将在转录方面进行研究， 生命周期中的时间和转录本的本地化， 蛋白质产品 全长，本地产品将表示内 哺乳动物细胞和针对这些蛋白质的抗体反应比较 在感染的老鼠体内。 抗血清和重组抗体 将产生这些蛋白质上的肽表位，并测试它们的 识别天然膜蛋白上的细胞外表位的能力 并抑制这些蛋白质的功能。 如果结果 有希望的是，将对其疫苗潜力进行体内测试。 这些研究应该为研究染色体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 此外，它们还应提供关于下列问题的进一步研究的基础： 使用血清暴露的溶酶体表面膜蛋白的潜力 作为疫苗的目标。

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.