Genetic Suppressors of Huntington's Disease in Mice

描述（由申请人提供）： 亨廷顿病（HD）是由亨廷顿基因（Ht）中的多聚谷氨酰胺扩增突变引起的破坏性神经退行性疾病。突变亨廷顿蛋白（mHt）发挥显性毒性，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。鉴定新药靶点的一种方法是通过遗传修饰剂研究。遗传=酵母、果蝇、C.线虫和哺乳动物细胞培养物已经产生了许多基因，这些基因可以被操纵以抑制突变亨廷顿蛋白毒性。然而，这些基因抑制哺乳动物脑中突变亨廷顿蛋白毒性的功效尚不清楚。该建议旨在建立一个小鼠遗传系统，可以容易地和系统地测试遗传抑制剂在体内的HD。 利用细菌人工染色体（Bacterial Artificial Chromosome，BAC）介导的转基因技术，我们成功地建立了内源性表达突变型亨廷顿蛋白（Huntingtin）的转基因小鼠模型。这些全长转基因创始人中的一些已经表现出早期和严重的运动缺陷。 这项建议的具体目标是： 1.表征HD的全长C模型并选择适合于遗传修饰剂研究的品系。 2.应用新开发的快速BAC修饰系统产生过表达两种修饰基因的小鼠，并在全长转基因模型中测试其抑制mHt毒性的功效。 如果证明是有效的，我们的BAC转基因系统可以很容易地扩大规模，系统地研究了大量的推定HD遗传修饰剂在体内。在小鼠中鉴定有效的遗传修饰剂可能为疾病发病机制和开发治疗药物的新靶点提供新的见解。

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.