COMPARATIVE GENOMICS OF PARASITIC NEMATODES

 描述（由申请人提供）：寄生线虫感染超过20亿人，导致显著的发病率和死亡率。寄生线虫基因组的表征提供了基本的分子信息，其可用于加速基础研究和新的诊断和治疗的开发，这是公共卫生的优先事项，因为目前可用的药物数量有限，对某些物种（例如，鞭虫）和增加抗药性。为此，我们已经建立了一个广泛的基因组数据库，测序和注释的基因组和转录组的线虫寄生虫的医学重要性，包括代表性的人类寄生虫，跨越主要的分类分支的线虫门。此外，我们集中分析生物化学途径保守和/或分类学限制和条件特异性，确定蛋白质，可能被证明是有用的药物靶点。该提案的三个目标是通过利用所产生的多维资源来进行旨在促进新疗法的发现和开发的系统生物学方法。首先，我们将重建肠道和丝虫寄生虫的代谢网络，分析将集中在分类学限制和差异表达的代谢途径作为驱虫药物的潜在目标的泛保守的阻塞点酶。其次，我们将进行药物敏感性测定，以测试我们的假设，并验证泛门靶点的预测广泛控制潜力。第三，我们将进行先导物优化，并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靶标抑制。我们整体方法的关键包括选择跨越动物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值的泛门代谢途径数据库），开发利用系统生物学和化学信息学进行靶标和药物优先级排序的优先级排序方案，然后进行实验验证，反过来，潜在客户的识别和优化。预期的结果将促进和促进新的干预措施的发现和开发，以治疗和控制这些重要的寄生虫，并降低其相关的发病率和死亡率。

 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.