Underlying mechanisms of schistosome/snail compatibility

描述(由申请人提供)：这项修订的提案寻求支持一项由研究人员发起的研究项目，该项目旨在研究人类寄生虫的中间宿主用来免疫攻击和杀死这些寄生虫的细胞和分子手段。广泛的长期目标是打破寄生虫向高危人群传播的循环。这项研究建立在申请人的实验室和其他实验室的最新进展基础上，并利用了比较功能基因组学的原理和一个新出现的宿主蜗牛基因组数据库。特别是，这项研究涉及参与细胞呼吸爆发的基因、信使RNA和蛋白质--这是一种复杂的途径，在这种复杂的途径中，宿主的防御细胞产生破坏性的活性氧和氮物种，这些物质至少在一定程度上对单个蜗牛抵抗感染的能力负责。这些目标涉及(I)基因：基因结构、转录和转录后编辑的细节，(Ii)蛋白质(包括酶活性)，(Iii)细胞反应的激活途径，以及(Iv)孢子囊死亡的最终原因。这些假设既容易处理，又合理地植根于已经证明的现象。实验材料包括对曼氏血吸虫标准株(俄勒冈州PR1)具有已知易感或抗药性表型的光面生物螺，曼氏血吸虫是一种人类肠道血吸虫病的病原体。资金将使一组研究人员能够在5年内集中精力解决这些问题。这些研究所获得的知识预计将增加实现该机构任务的可能性--防止血吸虫寄生虫(S.mansoni)未来向人类传播--通过中断其中间宿主光滑杆菌的寄生虫的生命周期来实现。这些目标将使用中间宿主蜗牛物种的近交系来实现，我们拥有这些中间宿主蜗牛物种的必要遗传信息(核酸序列数据)，并且现在可以使用敏感的报告程序和有效的多种细胞功能抑制剂。公共卫生相关性：在流行地区(约有2亿人感染的70个国家)的人群中，这种(人类血吸虫)寄生虫的负担相当严重。受感染的人的认知水平较低(更难学习)，做体力工作的精力较弱。因此，这项工作的最终目的是打破血吸虫传播的循环，可通过增进健康和提高生活质量(提高学习和从事体力工作的能力)来促进公益。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The burden of this (human blood-fluke) parasite is considerable among human populations in endemic regions (>70 countries in which ~200,000,000 people are infected). Infected individuals experience lower levels of cognition (it is harder to learn), and of energy to do physical work. Hence this work, in which the ultimate aim is to break the cycle of schistosome transmission, may contribute to public welfare through enhancement of health and of the quality of life (improved capacities to learn and to do physical work).