Can drug targets from parasitic nematodes be usefully expressed in C. elegans?

寄生线虫的药物靶标能否在秀丽隐杆线虫中有效表达?

基本信息

  • 批准号:
    8302014
  • 负责人:
  • 金额:
    $ 23.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-02-15 至 2014-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Parasitic nematodes cause many of the most prevalent Neglected Infections of Poverty and Neglected Tropical Diseases. Programs for the elimination and control of these infections rely on mass administration of anthelmintic drugs, but resistance may become a problem and there is an inadequate supply of alternatives. Current experimental methods for studying the genetics of anthelmintic resistance, and for screening potential new drugs, are inadequate, due to the inherent difficulties in working with these organisms. Functional expression of parasite genes in the free-living species, Caenorhabditis elegans, has the potential to address these problems but the complexity of the drug targets may cause difficulties. Most anthelmintics target ligand-gated ion channels, such as the ligand-gated ion channels (LGIC). The LGIC are multi-subunit proteins, encoded by a large gene family in C. elegans, and dependent on many other gene products for their correct assembly and trafficking. In addition, the size and composition of the gene family varies greatly between nematode species. We will focus on two well-characterized LGIC that are widely conserved in nematodes - the glutamate-gated chloride channel (GluCl) formed by the AVR-14B gene product and the levamisole-sensitive receptor found at the neuromuscular junction. We have previously shown that we can express AVR-14B from parasitic nematodes in C. elegans, and will now optimize the method for doing this. We will attempt to rescue mutations in the C. elegans unc-29 and unc-38 genes, which encode subunits of the levamisole receptor, via the expression of the parasite orthologues under the control of the C. elegans promoters. The use of drug resistance, caused by the unc-29 and unc-38 mutations, as a marker provides a quick and convenient first screen for these experiments. If the parasite cDNAs do rescue the drug resistance phenotype, then this will indicate that C. elegans is a suitable host for the expression and study of candidat resistance alleles. Eventually we may be able to reconstruct a complete 'parasite' nAChR in a C. elegans host, which could then be exploited for detailed study of the comparative pharmacology and physiology of these receptors and potentially form the basis of parasite-specific drug screens. Our specific objectives are; 1) To develop an optimized protocol for the expression of parasite ion channel cDNAs in C. elegans; 2) To measure the anthelmintic sensitivity of transgenic worm strains; 3) To directly record the properties of the muscle nicotinic receptors from transgenic strains expressing parasite nicotinic subunits. This project aims to reduce our reliance on infected animals and humans as a source of biological material and provide an important new way of studying the genetics of human parasites, which we would extend to other identified drug targets. PUBLIC HEALTH RELEVANCE: Parasitic nematodes infect billions of people worldwide, and millions in the United States. These organisms are difficult to study, because of their biology, and as a result we know little about their genetics, especially in relation to drug resistance, and how this might be affected by current drug administration programs. The goal of this proposal is to see if we can use a well-known laboratory model, Caenorhabditis elegans to study genes from parasites, to better understand drug resistance and to develop new methods for to help the development of new drugs.
描述(申请人提供):寄生线虫引起许多最普遍的被忽视的贫困和被忽视的热带疾病的感染。消除和控制这些感染的计划依赖于大规模使用驱虫药,但耐药性可能成为一个问题,替代药物供应不足。目前研究驱虫药耐药性的遗传学和筛选潜在新药的实验方法是不充分的,这是因为与这些生物合作的内在困难。在自由生活的物种秀丽线虫中进行寄生虫基因的功能性表达,有可能解决这些问题,但药物靶标的复杂性可能会造成困难。大多数驱虫药以配体门控离子通道为靶标,如配体门控离子通道(LGIC)。LGIC是一种多亚基蛋白质,由线虫的一个大基因家族编码,依赖于许多其他基因产物的正确组装和运输。此外,基因家族的大小和组成在不同的线虫物种之间也有很大差异。我们将关注两个在线虫中广泛保守的特征良好的LGIC-由AVR-14B基因产物形成的谷氨酸门控氯通道(GluCl)和位于神经肌肉连接处的左旋咪唑敏感受体。我们之前已经证明我们可以在线虫中表达寄生线虫的AVR-14B,现在将优化实现这一目的的方法。我们将试图通过在线虫启动子的控制下表达寄生虫同源基因来挽救线虫UNC-29和UNC-38基因的突变,这些基因编码左旋咪唑受体的亚单位。使用由UNC-29和UNC-38突变引起的耐药性作为标记,为这些实验提供了快速和方便的第一次筛查。如果寄生虫的cDNA确实挽救了耐药表型,那么这将表明线虫是表达和研究念珠菌耐药等位基因的合适宿主。最终,我们可能能够在线虫宿主中重建一个完整的“寄生虫”nAChR,然后可以利用它来详细研究这些受体的比较药理学和生理学,并可能形成寄生虫特异性药物筛选的基础。我们的具体目标是:1)建立一种在线虫中表达寄生虫离子通道cDNA的优化方法;2)测量转基因虫株的驱虫敏感性;3)直接记录表达寄生虫烟酸亚基的转基因菌株的肌肉烟碱受体的特性。该项目旨在减少我们对受感染的动物和人类作为生物材料来源的依赖,并为研究人类寄生虫的遗传学提供一种重要的新方法,我们将把这种方法扩展到其他已确定的药物靶标。 公共卫生相关性:全世界有数十亿人感染寄生线虫,美国有数百万人感染。这些生物很难研究,因为它们的生物学,因此我们对它们的遗传学知之甚少,特别是与抗药性有关的遗传学,以及 这可能会受到当前药物管理计划的影响。这项提议的目的是看看我们是否可以利用著名的实验室模型--秀丽隐杆线虫来研究寄生虫的基因,更好地了解耐药性,并开发新的方法来帮助开发新药。

项目成果

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Adrian J Wolstenholme其他文献

Adrian J Wolstenholme的其他文献

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{{ truncateString('Adrian J Wolstenholme', 18)}}的其他基金

Trafficking of parasitic nematode ion channels
寄生线虫离子通道的贩运
  • 批准号:
    9165333
  • 财政年份:
    2016
  • 资助金额:
    $ 23.46万
  • 项目类别:
Trafficking of parasitic nematode ion channels
寄生线虫离子通道的贩运
  • 批准号:
    9285709
  • 财政年份:
    2016
  • 资助金额:
    $ 23.46万
  • 项目类别:
Anthelmintics: From discovery of new drugs to modes of action and resistance
驱虫药:从新药的发现到作用方式和耐药性
  • 批准号:
    8646022
  • 财政年份:
    2014
  • 资助金额:
    $ 23.46万
  • 项目类别:
The antifilarial activity of ivermectin and diethylcarbamizine
伊维菌素和二乙基卡巴嗪的抗丝虫活性
  • 批准号:
    8756401
  • 财政年份:
    2014
  • 资助金额:
    $ 23.46万
  • 项目类别:
The antifilarial activity of ivermectin and diethylcarbamizine
伊维菌素和二乙基卡巴嗪的抗丝虫活性
  • 批准号:
    8901920
  • 财政年份:
    2014
  • 资助金额:
    $ 23.46万
  • 项目类别:
Can drug targets from parasitic nematodes be usefully expressed in C. elegans?
寄生线虫的药物靶标能否在秀丽隐杆线虫中有效表达?
  • 批准号:
    8422969
  • 财政年份:
    2012
  • 资助金额:
    $ 23.46万
  • 项目类别:

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