Genetic Suppressors of Huntington's Disease in Mice

描述(由申请人提供)： 亨廷顿病(HD)是一种由亨廷顿蛋白基因(Ht)多聚谷氨酰胺扩增突变引起的破坏性神经退行性疾病。突变的亨廷顿(Huntingtin，MHT)具有明显的毒性，可导致选择性神经元功能障碍和变性。目前，HD的有效药物靶点很少。识别新药靶点的一种方法是通过基因修饰物研究。在酵母、果蝇、线虫和哺乳动物细胞培养中进行的遗传修饰筛选已经产生了许多可以被操纵的基因，可以抑制突变的亨廷顿毒素。然而，这些基因抑制哺乳动物大脑中突变的亨廷顿毒素的效果尚不清楚。这项建议旨在建立一种小鼠遗传系统，可以在体内容易和系统地测试HD的遗传抑制基因。 利用一种相对新颖的小鼠遗传技术，即细菌人工染色体(BAC)介导的转基因技术，我们成功地建立了在内源调控下表达全长突变体Huntingtin的新型转基因小鼠模型。这些全长转基因创始人中的一些人已经表现出早期严重的运动障碍。 这项建议的具体目的是： 1.鉴定全长C模型，筛选适合于遗传修饰研究的品系。 2.应用新开发的BAC快速修饰系统，建立高表达两种修饰基因的小鼠模型，并在全长转基因模型中检测其对MHT毒性的抑制作用。 如果被证明是有效的，我们的BAC转基因系统很容易扩大规模，在体内系统地研究大量可能的HD遗传修饰物。在小鼠中鉴定有效的遗传修饰物可能会为疾病发病机制提供新的见解，并为开发治疗药物提供新的靶点。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disease caused by a polyglutamine expansion mutation in the Huntingtin gene (Ht). The mutant Huntingtin (mHt) exerts dominant toxicity to cause selective neuronal dysfunction and degeneration. Currently, there are very few valid drug targets for HD. One method to identify new drug targets is through genetic modifier studies. Genetic = modifier screenings in Yeast, Drosophila, C. elegans and mammalian cell culture have produced a number of genes that can be manipulated to suppress mutant Huntingtin toxicity. However, the efficacy of these genes to suppress mutant Huntingtin toxicity in the mammalian brain is unclear. This proposal seeks to establish a mouse genetic system that can readily and systematically test genetic suppressors for HD in vivo. Using a relatively novel mouse genetic technology, called Bacterial Artificial Chromosome (BAC) mediated transgenics, we have succeeded in creating novel transgenic mouse models of HI) expressing full-length mutant Huntingtin under the endogenous regulation. Some of these full-length transgenic founders have already demonstrated early and severe motor deficits. The specific aims of this proposal are to: 1. Characterize the fulfull-lengthC models of HD and select lines suitable for genetic modifier studies. 2. Apply the newly developed rapid BAC modification system to generate mice over expressing two modifier genes and to test their efficacy in suppressing mHt toxicity in the full-length transgenic models. If proven effective, our BAC transgenic System can readily be scaled up to systematically study a large number of putative HD genetic modifiers in vivo. Identification of effective genetic modifiers in mice may provide novel insights into disease pathogenesis and new targets to develop therapeutics.