DEVELOPMENT OF NUCLEAR RECEPTORS AS ANTHELMINTIC TARGETS

全世界有超过10亿人被寄生线虫感染，寄生线虫导致各种使人衰弱的营养、胃肠道和其他疾病。许多此类感染无法用现有药物治愈，预防性疫苗接种对这些复杂的寄生虫尚不可行。该项目的长期目标是确定新的抗线虫化合物，以满足人类健康的需要。模式自由生活线虫秀丽隐杆线虫的完整基因组序列揭示了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NR已经成为药物治疗的富有成效的来源。必需的线虫NR将是有前途的目标，选择性抗线虫药物发现的努力。初步数据来自C。elegans已经鉴定出线虫生存力所必需的NR基因。本项目第一阶段的具体目标是：（1）鉴定必需C的同系物。elegans NRs的研究，以验证这些NRS作为候选的一般杀线虫剂靶标。(2)建立基于细胞的杀线虫剂NR活性化学调节剂的测定方法，为II期高通量化学筛选的发展提供基础。拟议的商业应用：拟议的第一阶段工作将建立基于细胞的测定线虫NR的活性，代表杀线虫剂开发工作的有前途的生物靶标。在第II阶段，这些试验将适用于高通量筛选，并扩展到其他感兴趣的线虫NR。由此产生的专有测定集合将允许针对来自多个线虫物种的一组NR进行化合物筛选。通过这些筛选鉴定的化合物将代表可以进一步开发为候选驱虫药物的先导物。

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.