COMPARATIVE GENOMICS OF PARASITIC NEMATODES

寄生线虫的比较基因组学 总结 寄生线虫感染超过20亿人，导致人类死亡和显著发病。 其基因组的表征提供了基本的分子信息， 和转化研究，这是一个公共卫生的优先事项，由于目前可用的数量有限， 药物，它们对某些物种的效力有限，耐药性不断增加。我们的长期目标是 促进发现和开发新的干预措施来治疗和控制这些重要的寄生虫。 迄今为止的进展已经建立了广泛的医学线虫寄生虫组学数据库 重要性，包括人类寄生虫跨越线虫类的主要分类分支。运用系统 生物学和进化原理，我们重建了不同线虫寄生虫的代谢网络， 发现了遗传上受限制和保守的代谢功能。这些结果导致我们的中央 假设靶向泛门保守代谢阻塞点酶的化合物具有较高的 尽管寄生虫的寄生模式多种多样，但仍有广泛控制的潜力;这一点很重要，因为 伴随感染在流行地区很普遍。为了验证这一点，我们已经确定了保守的目标， 具有广谱防治潜力的化合物。极端环境下寄生虫的表型筛选 萨根尼证实了我们的预测。最后，建立了线虫特异性分子生物学数据库 特性之间的阻塞点酶的目标和实验表明，活性位点的差异， 支持开发选择性抑制剂的可行性。 我们提出的目标是在我们取得重大进展的基础上，利用并进一步改进我们的 多维资源（目标1），以缩小组学研究和可操作药物发现之间的差距。 利用寄生虫特异性活性位点的特征，我们将使用合理的设计和药物化学， 优化三个已确定目标类别的先导抑制剂（目标2）。最有效的四种化合物 体外钩虫将在体内筛选，然后进行优化，包括测试各种药代动力学 改进以增强疗效和持久性（目标3）。此外，由于主要的肠道线虫 具有引起病理性肺部病变的迁移性经肺动脉阶段，我们将测试电极导线的有效性 预防早期寄生阶段，这对减少这种不可逆转的发病率至关重要。最后，我们将扩大 我们的主要铅化合物筛选，以证明泛钩虫和泛肠道潜力（目标4）。 这一贡献是重要的，因为这一进展填补了代谢功能的知识空白 这是这些寄生虫生存所必需的。代谢阻塞点酶的合理靶向， 驱虫剂是完全新颖的，利用特定的泛门保守靶标的概念也是如此 开发一种对线虫具有广谱功效的单一驱虫剂。总体而言，我们 拟议的研究有可能为改善全球健康提供实际成果。

Comparative Genomics of Parasitic Nematodes Summary Parasitic nematodes infect over two billion people, causing mortality and significant morbidity in humans. Characterization of their genomes provides fundamental molecular information essential for accelerating basic and translational research, which is a public health priority due to the limited number of currently available drugs, their limited efficacy against some species and increasing drug resistance. Our long-term goal is to facilitate the discovery and development of novel interventions to treat and control these important parasites. Progress to date has established an extensive omics database for nematode parasites of medical importance, including human parasites spanning the major taxonomic clades of Nematoda. Using systems biology and evolutionary principles we reconstructed metabolic networks for diverse nematode parasites and discovered phylogenetically restricted and conserved metabolic functions. These results led to our central hypothesis that compounds targeting pan-phylum conserved metabolic chokepoint enzymes have a high potential for broad control despite the parasites' diverse modes of parasitism; which is important since concomitant infection is prevalent in endemic areas. To test this, we have identified conserved targets and compounds with broad-spectrum control potential. Phenotypic screening of parasites at the extremes of the phylogeny validated our predictions. Finally, we established a database of nematode-specific molecular features among the chokepoint enzyme targets and experimentally demonstrated that active-site differences support the feasibility of developing selective inhibitors. Our proposed aims build on our significant progress by taking advantage of and further improving our multi-dimensional resources (Aim 1) to close the gap between omics research and actionable drug discovery. Leveraging the parasite specific active-site features, we will use rational design and medicinal chemistry to optimize the lead inhibitors of the three identified target classes (Aim 2). The four compounds most effective in hookworm in vitro will be screened in vivo, followed by optimization including testing various pharmacokinetic modifications for enhanced efficacy and persistence (Aim 3). Furthermore, since major intestinal nematodes have migratory transpulmonary stages that cause pathological lung lesions, we will test efficacy of the leads against early parasitic stages, which is essential to reducing this irreversible morbidity. Finally, we will expand our primary lead compound screen to demonstrate pan-hookworm and pan-intestinal potential (Aim 4). This contribution is significant since the progress fills the knowledge gap in metabolic functions essential for survival of these parasites. The rational targeting of metabolic chokepoint enzymes as anthelminthic agents is thoroughly novel, as is the concept of utilizing a specific pan-phylum conserved target to develop a single anthelmintic with broad spectrum efficacy against nematodes at large. Collectively, our proposed research has the potential to provide practical results for global health improvement.