DEVELOPMENT OF NUCLEAR RECEPTORS AS ANTHELMINTIC TARGETS

全世界有超过10亿人被寄生线虫感染，这些线虫会导致各种令人衰弱的营养、胃肠道和其他疾病。许多这种感染不能用现有的药物治愈，对这些复杂的寄生虫进行预防性疫苗接种还不可行。该项目的长期目标是确定新的抗线虫化合物，以满足这一人类健康需求。模式自由生活线虫秀丽线虫的全基因组序列包含260个编码核受体(NR)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。许多NRS已经成为药物治疗的富有成效的来源。基本线虫NRs将成为选择性抗线虫药物发现的有希望的靶标。线虫研究的初步数据已经确定了线虫生存所必需的NR基因。本项目第一阶段的具体目标是：(1)鉴定寄生线虫中必需的线虫NRs的同源物，验证这些NRs作为候选的通用杀线虫靶标。(2)建立针对杀线虫NR活性的化学调节剂的基于细胞的检测方法，为第二阶段高通量化学筛选的开发提供基础。拟议的商业应用：拟议的第一阶段工作将建立基于细胞的线虫NRs活性检测，为杀线虫开发工作提供有前景的生物靶标。在第二阶段，这些检测方法将适用于高通量筛选，并扩展到其他感兴趣的线虫NRs。由此产生的专有化验集合将允许对来自多个线虫物种的一组NRs进行化合物筛选。通过这些筛选确定的化合物将代表可以进一步开发为候选驱虫药的线索。

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.