DEVELOPMENT OF NUCLEAR RECEPTORS AS ANTHELMINTIC TARGETS

全世界有超过10亿人感染了寄生虫，导致各种使人衰弱的营养、胃肠道和其他疾病。许多这类感染无法用现有药物治愈，而且对这些复杂的寄生虫还不可能进行预防性疫苗接种。该项目的长期目标是确定新的抗线虫化合物，以满足人类健康的需要。模拟自由生活线虫秀丽隐杆线虫的全基因组序列显示260个编码核受体转录因子的基因。这些基因中的大多数定义了线虫特有的NR类别。许多nr已经成为药物治疗的富有成效的来源。必要的线虫NRs将是选择性抗线虫药物发现工作的有希望的目标。对秀丽隐杆线虫的初步研究数据已经确定了NR基因对线虫的生存能力至关重要。本项目第一阶段的具体目标是：(1)鉴定寄生线虫中秀丽隐杆线虫必需NRs的同源物，验证这些NRs作为一般杀线虫剂的候选靶点。(2)建立基于细胞的杀线虫剂NR活性化学调节剂的检测方法，为开发高通量的II期化学筛选奠定基础。拟议的商业应用：拟议的I期工作将建立基于细胞的测定线虫NRs活性的方法，这代表了杀线虫剂开发工作中有希望的生物靶点。在第二阶段，这些检测将适用于高通量筛选，并扩展到其他感兴趣的线虫nr。由此产生的专有检测集合将允许对来自多种线虫物种的一系列NRs进行化合物筛选。通过这些筛选确定的化合物将成为进一步开发候选驱虫药的线索。

Over one billion people worldwide are infected by parasitic nematodes that cause various debilitating nutritional, gastrointestinal, and other diseases. Many such infections are not curable with existing medications, and preventive vaccinations are not yet feasible for these complex parasites. The long-term goal of this project is to identify new anti- nematode compounds that will fulfill this human health need. The complete genome sequence of the model free-living nematode Caenorhabditis elegans reveals 260 genes encoding nuclear receptor (NR) transcription factors. The majority of these genes define NR classes unique to nematodes. Many NRs have been fruitful sources of drug therapies. Essential nematode NRs will be promising targets for selective anti-nematode drug discovery efforts. Preliminary data from work with C. elegans has identified NR genes essential for nematode viability. The specific aims for Phase I of this project are: (1) Identify homologues of the essential C. elegans NRs in parasitic nematodes, to validate these NRS as candidate general nematocide targets. (2) Establish cell-based assays for chemical modulators of nematocide NR activity, to provide a foundation for development of high-throughput chemical screens in Phase II. PROPOSED COMMERCIAL APPLICATIONS: The proposed Phase I efforts will establish cell-based assays for the activity of nematode NRs that represent promising biological targets for nematocide development efforts. During Phase II these assays will be adapted for high-throughput screening and extended to additional nematode NRs of interest. The resulting proprietary collection of assays will allow compound screening against a battery of NRs from multiple nematode species. Compounds identified by these screens will represent leads that can be further developed as candidate anthelmintic drugs.