Underlying mechanisms of schistosome/snail compatibility

项目总结/摘要。 这一修订提案寻求对一个由联合国发起的研究项目的支持， 人类寄生虫的中间宿主使用的细胞和分子手段， 免疫攻击并杀死这些寄生虫。广泛的长期目标是 打破寄生虫向高危人群传播的循环。研究 基于申请人实验室和其他实验室的最新进展， 利用比较功能基因组学的原理和新兴的数据库， 宿主蜗牛的基因组特别是，这项研究涉及基因，信使RNA 和参与细胞呼吸爆发的蛋白质-一个复杂的途径， 破坏性的活性氧和氮物种是由防御细胞产生的。 宿主，至少部分负责个别蜗牛的能力， 抵抗感染。这些目标涉及处理以下问题的合理假设：（i）基因： 基因结构、转录和转录后编辑，（ii）蛋白质（包括 酶活性），（iii）细胞反应的活化途径，以及（iv） 孢子囊死亡。这些假设都是易于处理的，并合理地锚定在 已经出现的现象。实验材料包括个人 光滑双脐螺（Biomphalaria glabrata）具有已知的对一种 曼氏血吸虫标准株（俄勒冈州PR 1），人血吸虫病病原体 肠血吸虫病资金将使一组研究人员能够集中精力 在这些问题上超过5年。从研究中获得的知识预计将 提高实现本机构使命的可能性-预防未来的 传播寄生虫（S。mansoni）对人类-完成 寄生虫在其中间宿主B中的生命周期中断。光滑的这些目标 将使用中间宿主蜗牛物种的近交系进行处理， 具有必要的遗传信息（核酸序列数据），并且其中 现在可以将敏感的报告基因用于多种细胞的有效抑制剂， 功能协调发展的

PROJECT SUMMARY/ABSTRACT. This revised proposal seeks support for an investigator-initiated research project into the cellular and molecular means used by intermediate hosts of a human parasite to immunologically attack and kill these parasites. The broad, long-term objective is to break the cycle of parasite transmission to at-risk human populations. The research builds on recent progress in the applicant's laboratory and other laboratories, and exploits the principles of comparative functional genomics and an emerging database for the host snail's genome. In particular, the research deals with genes, messenger RNAs and proteins involved in the cellular respiratory burst - a complex pathway in which damaging reactive oxygen and nitrogen species are produced by the defense cells of the host and which are at least partialy responsible for the capacity of individual snails to resist infection. The aims address plausible hypotheses dealing with (i) genes: details of gene structure, transcription and post-transcriptional editing, (ii) proteins (including enzyme activities), (iii) activation pathways for cell responses, and (iv) ultimate causes of death of sporocysts. The hypotheses are both tractable and reasonably anchored in already demonstrated phenomena. Experimental materials include individual Biomphalaria glabrata snails with known susceptible or resistant phenotypes to a standard strain (Oregon PR1) of Schistosoma mansoni, a causative agent of human intestinal schistosomiasis. Funds will enable a team of researchers to focus their efforts on these issues over 5 years. Knowledge resulting from the studies is expected to enhance the likelihood of achieving a mission of this agency - prevention of future transmission of schistosome parasites (S. mansoni) to humans - accomplished by interruption of the parasite's life cycle in its intermediate host, B. glabrata. These goals will be addressed using inbred strains of the intermediate host snail species for which we have the necessary genetic information (nucleic acid sequence data) and in which it is now feasible to use sensitive reporters for and efficient inhibitors of a variety of cell functions.