COMPARATIVE GENOMICS OF PARASITIC NEMATODES

 描述(申请人提供)：寄生线虫感染超过20亿人，导致严重的发病率和死亡率。寄生线虫基因组的特征提供了基本的分子信息，可用于加速基础研究和新的诊断和治疗方法的开发，由于目前可用的药物数量有限，对某些物种(如鞭虫)的疗效有限，以及不断增加的抗药性，这些信息是公共卫生的优先事项。为此，我们通过对具有重要医学意义的线虫的基因组和转录本进行测序和注释，建立了一个广泛的基因组数据库，其中包括跨越线虫门主要分类支系的代表性人类寄生虫。此外，我们重点分析了保守的和/或分类上受限的和特定于条件的生化途径，识别可能被证明是有用的药物靶点的蛋白质。这项提议的三个目标是在我们的进展的基础上，利用所产生的多维资源，采取旨在促进新疗法的发现和发展的系统生物学方法。首先，我们将重建肠道寄生虫和丝虫寄生虫的代谢网络，并将分析重点放在分类限制和差异表达的代谢途径中的泛保守的节点酶，作为驱虫药的潜在靶点。其次，我们将进行药物敏感性分析来验证我们的假设，并验证泛门目标的预测广泛控制潜力。第三，我们将进行先导优化，证明线虫代谢酶抑制剂的效力和选择性增加，然后在体外和体内验证目标抑制。我们整体方法的关键包括选择跨越该门进化极端的寄生虫物种(支持创建具有最广泛范围和最佳预测价值的泛门类代谢途径数据库)，开发利用系统生物学和化学信息学进行靶向和药物优先排序的优先方案，然后进行实验验证，进而识别和优化线索。预期结果将促进和促进新干预措施的发现和发展，以治疗和控制这些重要寄生虫，并降低其相关发病率和死亡率。

 DESCRIPTION (provided by applicant): Parasitic nematodes infect more than two billion people, causing significant morbidity and mortality. Characterization of the genomes of parasitic nematode provides fundamental molecular information that can be used to accelerate basic research and the development of new diagnostics and therapeutics, which are a public health priority due to the limited number of currently available drugs, the limited efficacy against some species (e.g., whipworm) and increasing anti-drug resistance. To that end, we have established an extensive genomic database by sequencing and annotating genomes and transcriptomes of nematode parasites of medical importance, including representative human parasites that span the major taxonomic clades in the phylum Nematoda. Furthermore, we focused analysis on biochemical pathways conserved and/or taxonomically restricted and condition-specific, identifying proteins that may prove useful as drug targets. The three aims of this proposal build on our progress by taking advantage of the generated multi-dimensional resource to undertake a systems biology approach aimed at promoting discovery and development of new therapeutics. First, we will reconstruct metabolic networks of both intestinal and filarial parasits, and analysis will focus on pan-conserved chokepoint enzymes in taxonomically restricted and differentially expressed metabolic pathways as potential targets for anthelmintic drugs. Second, we will perform drug-sensitivity assays to test our hypothesis and validate the predicted broad control potential of the pan-phylum targets. Third, we will perform lead optimization and demonstrate increased potency and selectivity of nematode metabolic enzyme inhibitors, followed by validation of target inhibition in vitro and in vivo. Keys to our overall approach include the selection of species of parasites that span the evolutionary extremes of the Phylum (supporting the creation of a pan-phylum metabolic pathway database with the broadest scope and optimal predictive value), the development of a prioritization protocol that leverages systems biology and cheminformatics for target and drug prioritization, followed by experimental validation and, in turn, identification and optimization of leads. The expected outcome will facilitate and promote the discovery and development of novel interventions to treat and control these important parasites and reduce their associated morbidity and mortality.