Metabolic network reconstruction in Filaria-Wolbachia symbiosis

丝虫-沃尔巴克氏菌共生的代谢网络重建

基本信息

  • 批准号:
    9292255
  • 负责人:
  • 金额:
    $ 16.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-06-10 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

The parasitic nematodes Onchocerca volvulus and Brugia malayi are responsible for devastating human filarial infections in the developing world such as river blindness and lymphatic filariasis. The awarding of the 2015 Nobel Prize in Physiology or Medicine to Campbell and Omura “for their discoveries concerning a novel therapy against infections caused by roundworm parasites" highlights the success of drugs such as Ivermectin for mass administration programs to control transmission of these parasites. However, current drugs only target the early larval stage (microfilaria) and have no effect on the adult worms, which can live 8-15 years. Consequently, drugs have to be administered for 30-40 years to eradicate the parasite from an infected population. The emergence of drug resistance has recently appeared as a real threat. Furthermore, in areas where O. volvulus is co-endemic with the agent responsible for loiasis (Loa loa), targeting the microfilaria can lead to serious adverse events. The “Achilles heel” of these worms is their endosymbiotic bacteria— Wolbachia—which are sensitive to antibiotics and thus offer a more expedient approach to controlling filarial infections. Killing the bacteria impedes parasite development, fecundity, and ultimately, survival within the human host. But using antibiotics as a mass drug administration strategy is not yet feasible. To date little is known concerning the respective contributions of each symbiotic partner to parasite growth. Here we propose a detailed characterization of the metabolic co-dependencies between the worm and its endosymbiont, to reveal critical enzymes that can be exploited for therapeutic intervention. This project seeks to use the genome information available for B. malayi, O. volvulus and their respective Wolbachia (wOv and wBm) to map out metabolic enzymes within pathways critical for microfilaria and adult parasite survival. We will launch a systematic analysis of metabolite flux within these pathways, integrating functional genomic datasets that capture the expression of enzymes by both worm and endosymbiont at key life cycle stages. Aim 1 will reconstruct combined filarial-Wolbachia metabolic pathways by integrating stage-specific RNAseq and metabolomics data to construct detailed mathematical models of parasite metabolism. We will then prioritize 5- 10 enzymes to validate model predictions in the most tractable model, B. malayi. Aim 2 will test the essentiality of these enzymes and examine resultant phenotypes by using RNA mediated interference (RNAi) to validate their essential functions on worm growth and survival. In parallel, for those enzymes with known chemical inhibitors, we will monitor the ability of such compounds to also impact worm growth and survival. Beyond their potential as lead compounds, such inhibitors may serve as molecular tools to further dissect pathway function. Our ultimate goal is to deliver a number of new candidate drug targets that may be exploited through existing drug development pipelines and lead to new macrofilaricidal drugs that target adult worms and can be used for elimination of filariasis.
寄生线虫盘尾丝虫和马来丝虫是造成毁灭性 发展中国家的人类丝虫病感染,如河盲症和淋巴丝虫病。授标 2015年诺贝尔生理学或医学奖授予坎贝尔和大村“,以表彰他们发现了 一种新的治疗蛔虫寄生虫引起的感染的方法”强调了药物的成功, 伊维菌素用于控制这些寄生虫传播的大规模管理计划。但目前的 药物只针对早期幼虫阶段(微丝蚴),对蠕虫没有影响,成虫可以活8-15 年因此,药物必须施用30-40年才能从感染者身上根除寄生虫。 人口抗药性的出现最近已成为一种真实的威胁。此外,在地区 其中O.肠扭转是共同流行的代理人负责洛阿洛阿(洛阿),针对微丝蚴可以 导致严重的不良事件。这些蠕虫的“致命弱点”是它们的内共生细菌- 沃尔巴克氏体-对抗生素敏感,因此提供了一种更有效的方法来控制丝虫病 感染.杀死细菌会阻碍寄生虫的发育、繁殖力,并最终阻碍寄生虫在环境中的生存。 人类宿主但使用抗生素作为大规模药物管理策略尚不可行。约会的时候, 已知关于每个共生伙伴对寄生虫生长的各自贡献。在这里我们建议 蠕虫和其内共生体之间的代谢相互依赖性的详细表征, 来揭示可用于治疗干预的关键酶。该项目旨在利用 B的基因组信息。malayi、马来岛O.肠扭转和它们各自的沃尔巴克氏体(wOv和wBm)来映射 在微丝蚴和成虫存活的关键途径中排除代谢酶。我们将发起一项 系统分析这些途径内的代谢物通量,整合功能基因组数据集, 捕获蠕虫和内共生体在关键生命周期阶段的酶表达。目标1将 通过整合阶段特异性RNAseq和 代谢组学数据来构建寄生虫代谢的详细数学模型。我们将优先考虑5- 10种酶来验证最易处理的模型B中的模型预测。马来语。目标2将测试必要性 这些酶,并检查所得表型,通过使用RNA介导的干扰(RNAi),以验证 它们对蠕虫生长和存活的重要作用。同时,对于那些具有已知化学物质的酶 抑制剂,我们将监测这些化合物也影响蠕虫生长和存活的能力。超出了他们 作为潜在的先导化合物,这些抑制剂可以作为分子工具,以进一步剖析途径的功能。 我们的最终目标是提供一些新的候选药物靶点,这些靶点可以通过现有的 药物开发管道,并导致新的杀大型丝虫药物,目标是蠕虫,可用于 消灭丝虫病。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Comparative transcriptomic analyses and single-cell RNA sequencing of the freshwater planarian Schmidtea mediterranea identify major cell types and pathway conservation.
  • DOI:
    10.1186/s13059-018-1498-x
  • 发表时间:
    2018-08-24
  • 期刊:
  • 影响因子:
    12.3
  • 作者:
    Swapna LS;Molinaro AM;Lindsay-Mosher N;Pearson BJ;Parkinson J
  • 通讯作者:
    Parkinson J
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Elodie Ghedin其他文献

Elodie Ghedin的其他文献

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{{ truncateString('Elodie Ghedin', 18)}}的其他基金

Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    8702534
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    9124711
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    8859388
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Molecular mechanisms of filarial endosymbiosis
丝虫内共生的分子机制
  • 批准号:
    8668614
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    8896419
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    9331417
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection
基于组学的流感感染年龄依赖性结果预测模型
  • 批准号:
    8725576
  • 财政年份:
    2013
  • 资助金额:
    $ 16.11万
  • 项目类别:
Pathogenesis of Obstruction/Emphysema and the Microbiome (POEM) in HIV
HIV 阻塞/肺气肿和微生物群 (POEM) 的发病机制
  • 批准号:
    7936916
  • 财政年份:
    2009
  • 资助金额:
    $ 16.11万
  • 项目类别:
Pathogenesis of Obstruction/Emphysema and the Microbiome (POEM) in HIV
HIV 阻塞/肺气肿和微生物群 (POEM) 的发病机制
  • 批准号:
    8119687
  • 财政年份:
    2009
  • 资助金额:
    $ 16.11万
  • 项目类别:
Pathogenesis of Obstruction/Emphysema and the Microbiome (POEM) in HIV
HIV 阻塞/肺气肿和微生物群 (POEM) 的发病机制
  • 批准号:
    8308436
  • 财政年份:
    2009
  • 资助金额:
    $ 16.11万
  • 项目类别:

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SBIR II 期:开发尿液试纸测试,可以指导复杂尿路感染的立即和适当的抗生素治疗
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