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Method of screening for agents inhibiting chloride intracellular channels
Method of screening for agents inhibiting chloride intracellular channels
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机译:筛选抑制氯化物细胞内通道的药物的方法
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摘要
The present invention isolates and characterizes the exc-4 gene of C. elegans, and identifies exc-4 as an orthologue of the human CLIC family of chloride intracellular channels. Accordingly, a nucleic acid having the sequence of SEQ ID NO.: 1 is disclosed, as well as recombinant vectors and host cells comprising the nucleic acid sequence of SEQ ID NO.: 1. Further, a number of screening methods are disclosed to identify putative agents that inhibit vertebrate, and preferably human, CLICs using C. elegans and exc-4 inhibition as a loss-of-function model for CLIC activity. Also disclosed is a method of determining whether a specific member of the CLIC gene family is involved in tubulogenesis, where the rescue of a C. elegans exc-4 excretory cell phenotype via expression of a transgenic CLIC gene of interest indicates that the CLIC gene of interest is involved in tubulogenesis. Finally, a method is disclosed of identifying putative vertebrate, and preferably human, CLIC inhibitors using transgenic C. elegans exc-4 mutant embryos, where expression of the transgene yields a CLIC product that rescues the exc-4 mutant phenotype. Agents of interest resulting in a reversionary exc-4 mutant phenotype are putative agents that inhibit CLIC expression or function.
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机译:本发明分离并鉴定了Ic的exc-4基因。线虫 I>,并将exc-4鉴定为人类CLIC氯化物细胞内通道家族的直向同源物。因此,公开了具有SEQ ID NO:1的序列的核酸,以及包含SEQ ID NO:1的核酸序列的重组载体和宿主细胞。此外,公开了多种筛选方法以鉴定使用IC抑制脊椎动物,最好是人类CLIC的推定药物。线虫 i>和exc-4抑制作为CLIC活性的功能丧失模型。还公开了一种确定CLIC基因家族的特定成员是否参与肾小管发生的方法,其中拯救了 C。秀丽线虫 I> exc-4的排泄细胞表型通过转基因目的CLIC基因的表达表明,目的CLIC基因参与了肾小管生成。最后,公开了一种使用转基因I C鉴定推定的脊椎动物,优选人CLIC抑制剂的方法。线虫 I> exc-4突变体胚胎,其中转基因的表达产生了一个CLIC产物,可挽救exc-4突变体表型。产生反向的exc-4突变表型的目标药物是抑制CLIC表达或功能的推定药物。
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