Trafficking of parasitic nematode ion channels

寄生线虫离子通道的贩运

• 批准号: 9165333
• 负责人: Adrian J Wolstenholme
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-03 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165333
• 关键词: Affect; Agonist; Amino Acid Sequence; Anthelmintics; Appearance; Belief; Caenorhabditis elegans; Cell Line; Cell Nucleus; Cell membrane; Cell surface; Cells; Cellular biology; Chloride Channels; Development; Dominant-Negative Mutation; Drug Receptors; Drug Targeting; Drug resistance; Endocytosis; Endosomes; Excision; Exposure to; Haemonchus; Human; Infection; Ion Channel; Ivermectin; Lead; Length; Levamisole; Ligands; Location; Lysosomes; Mediating; Membrane; Modeling; Mutate; Nematoda; Nervous system structure; Nicotine; Nicotinic Receptors; Parasite resistance; Parasites; Parasitic nematode; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Population; Potassium Channel; Process; Property; Proteins; Pyrantel; Recycling; Reporting; Resistance; Role; Signal Transduction; Testing; Transgenic Organisms; Up-Regulation; Vaccines; Veterinary Medicine; Work; health economics; in vitro testing; in vivo; insight; late endosome; novel; receptor; receptor function; trafficking; uptake

Parasitic nematodes infect a large proportion of the world's population and contribute to the continuing poor health and economic under-development of the affected populations. Control and the planned elimination of these infections is dependent on effective anthelmintic drugs as no vaccines are available. At present, it is not properly understood how the drugs work and resistance to them is an increasing threat. It is known that many of the drugs act at receptors and ion channels in the parasites nervous system. The aim of this proposal is to test the hypothesis that the normal processes by which these receptors and ion channels are directed to their correct locations within the cell may be subverted in resistant parasites and may be affected by the drugs themselves. Two drugs will be the focus of the studies, levamisole and emodepside. Levamisole acts at a subset of nicotinic acetylcholine receptors and emodepside at SLO-1 potassium channels. Truncated forms of subunits of the levamisole receptor have been identified and their ability to affect the location and function of the receptors will be tested in vitro and in vivo. Specific amino-acid sequence motifs that cause endocytosis from the plasma membrane are present in some truncated levamisole receptor subunits, but not the full-length versions – the contribution of these motifs to altered trafficking will be examined. Similar motifs are present in SLO- 1 from some parasite species, but not others, which suggests that the function of the channel may be subtly different between species. This may be reflected in slightly different effects of emodepside. This will be tested by careful examination of the sub- cellular expression pattern of the different SLO-1 channels, and by testing the effects of mutating these motifs on that expression pattern. The project will reveal new aspects of the cell biology of drug targets in parasitic nematodes and provide new insights into how these may be perturbed in resistance.

寄生线虫感染了世界上很大一部分人口，并导致 受影响者的健康状况持续不佳，经济不发达， 人口。控制和有计划地消除这些感染取决于 有效的驱虫药物，因为没有疫苗可用。目前， 了解药物的工作原理，对它们的耐药性是一个日益严重的威胁。是 已知许多药物作用于寄生虫的受体和离子通道 神经系统这项建议的目的是检验假设，即正常 这些受体和离子通道被引导到它们的正确的 细胞内的位置可能在抗性寄生虫中被破坏， 毒品本身。两种药物将是研究的重点，左旋咪唑和 表情符号。左旋咪唑作用于烟碱乙酰胆碱受体的亚类， 在SLO-1钾通道中。亚基的截短形式 左旋咪唑受体已被确定，它们的能力，影响的位置和 将在体外和体内测试受体的功能。特异性氨基酸序列 引起质膜内吞作用的基序存在于一些细胞中， 截短的左旋咪唑受体亚基，但不是全长版本-贡献 将审查这些动机与改变贩运的关系。类似的基序也存在于SLO中- 1从一些寄生虫物种，但不是其他人，这表明，功能的 不同物种之间的通道可能略有不同。这可能反映在轻微的 Emodepside的不同效果这将通过仔细检查子- 不同SLO-1通道的细胞表达模式，并通过测试 在表达模式上改变这些基序。该项目将揭示新的方面 药物靶向寄生线虫的细胞生物学，并提供了新的见解 这些电阻可能会受到干扰。