SCHISTOSOMA MANSONI DEFENSE GENES: IDENTIFICATION AND EXPLOITATION IN THE DEVELO

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 血吸虫病是一种血管内感染，影响约2.07亿人。吡喹酮是唯一广泛用于治疗这种疾病的药物，但该药物不能杀死幼年血吸虫。因此，单剂吡喹酮不太可能打破感染循环。此外，一些血吸虫野外株可能对这种药物产生抗药性。 我们研究的目的是确定可以作为靶点的血吸虫蛋白，从而设计出一种新的、更有效的药物。它最初的计划是在由于压力而受到差异调控的基因产品中识别这样的靶点。我们最初的压力源之一是吡喹酮，作为最近获得的微阵列数据的结果，我们专注于试图阐明这种药物的作用机制。为了实现这一目标，我们一直在使用基于活性的蛋白质图谱技术和吡喹酮治疗的成熟血吸虫的微阵列分析。这些方法提出了几种吡喹酮杀死成虫的途径，目前正在探索中。此外，PI访问了肯尼亚的基苏木，并用从丢弃的患者粪便中提取的野外分离株感染了蜗牛和老鼠。这些分离株将被用来确定潜在的治疗靶点是否在野外菌株中表达，并用于评估耐药性。 确定吡喹酮作用的分子途径(S)将为血吸虫对吡喹酮的敏感性如何变化以及如何开发新一代疗法提供有价值的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schistosomiasis is an intravascular infection that affects approximately 207 million people. Praziquantel is the only drug in widespread use for treatment of the disease but the drug does not kill juvenile schistosomes. As a result, a single dose of praziquantel is unlikely to break the cycle of infection. In addition, some field strains of schistosomes may be developing resistance to the drug. The aim of our study is to identify Schistosoma proteins that can be used as targets against which a new, more effective drug can be designed. It was originally planned to identify such targets among gene products that were differentially regulated as a result of stress. One of our original stressors was praziquantel and as a result of microarray data obtained recently we have focused on the trying to elucidate the mechanism of action of this drug. To fulfill this aim we have been using activity based protein profiling techniques and microarray analysis of praziquantel treated mature schistosomes. These approaches have suggested several pathways by which praziquantel may kill adult worms and which are currently being explored. In addition, the PI visited Kisumu, Kenya and has infected snails and mice with field isolates derived from discarded patient feces. These isolates will be used to determine whether potential therapeutic targets are expressed in field strains and to assess drug resistance. Identifying the molecular pathway(s) on which praziquantel acts should provide valuable insights into how variable schistosome praziquantel sensitivities evolve and how a new generation of therapeutics might be developed.