SCHISTOSOMA MANSONI DEFENSE GENES: IDENTIFICATION AND EXPLOITATION IN THE DEVELO

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 血吸虫病是一种血管内感染，影响约2.07亿人。吡喹酮是唯一广泛使用的治疗该病的药物，但这种药物不会杀死青少年脊髓灰质炎病毒。因此，单剂量吡喹酮不太可能打破感染循环。此外，一些野毒株的Escherosomes可能会对药物产生耐药性。 我们研究的目的是鉴定血吸虫蛋白质，这些蛋白质可用作设计新的更有效药物的靶点。最初的计划是在由于压力而受到差异调节的基因产物中鉴定这样的靶点。我们最初的应激源之一是吡喹酮，由于最近获得的微阵列数据，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，我们一直在使用活性为基础的蛋白质谱技术和吡喹酮处理的成熟染色体的微阵列分析。这些方法提出了吡喹酮可能杀死蠕虫的几种途径，目前正在探索这些途径。此外，PI访问了肯尼亚的基苏穆，并使用来自废弃患者粪便的田间分离株感染了蜗牛和小鼠。这些分离株将用于确定潜在的治疗靶点是否在田间菌株中表达，并评估耐药性。 确定吡喹酮作用的分子途径，应提供有价值的见解，如何可变的过敏性吡喹酮敏感性演变，以及如何开发新一代的治疗方法。

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.