Reversible conditional models for Huntington's disease

亨廷顿病的可逆条件模型

• 批准号: 8223374
• 负责人: Scott Zeitlin
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223374
• 关键词: 1 year old; Actins; Adult; Affect; Age; Age-Months; Alleles; Behavioral; Behavioral Symptoms; Conceptions; Development; Disease; Disease model; Elderly; Embryo; Epitopes; Event; Exhibits; Financial compensation; Functional disorder; Gene Expression; Genes; Hereditary Disease; Homologous Gene; Huntington Disease; Isopropyl Thiogalactoside; Knock-out; Lac Repressors; Lactose; Life; Modeling; Motor; Mus; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Patients; Phenotype; Prosencephalon; Role; Safety; Severities; Stretching; Symptoms; Testing; Therapeutic; Time; Transgenes; Treatment Efficacy; Trinucleotide Repeats; Withdrawal; analog; base; critical period; disease phenotype; drinking water; gain of function; human Huntingtin protein; middle age; mouse model; mutant; nestin protein; neurogenesis; novel; polyglutamine; postnatal; promoter; synaptogenesis

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a dominant hereditary disease that is caused by the expansion of a CAG triplet repeat encoding a stretch of polyglutamine (polyQ) within Huntingtin (Htt), the protein product of the HD gene. The expansion of the Htt polyQ stretch confers a deleterious gain-of-function while simultaneous loss of normal Htt function can also contribute to pathogenesis. In HD and other adult onset neurodegenerative diseases, evidence is accumulating suggesting that dysfunction during development can contribute to later pathogenesis. Alternatively, compensatory mechanisms acting during development can delay the onset of neurodegeneration and motor/behavioral symptoms. Our overall objective is to use novel repressible/inducible knockin mouse models for HD to explore the role of developmental expression and compensation in the progression of Huntington's disease, and to determine if there are critical times during development or at different ages in the adult, when normal htt expression must be maintained. To this end, we are developing knockin mouse models that express either normal (7Q) or mutant (140Q) versions of the mouse HD gene (Hdh) that have lactose operator (LacO) sequences inserted within their promoters. When these HdhLacO alleles are expressed together with a transgene encoding a version of the bacterial lactose repressor (LacIR) that functions in mice (HdhLacO-3xFLAG-7Q/-; -actin LacIR-tg and HdhLacO-140Q/+; -actin LacIR-tg mice, respectively), wild-type or mutant htt expression can be turned-on or turned-off by administering or withdrawing isopropyl - D thiogalactoside (IPTG, a lactose analog) in the mouse's drinking water. In Aim 1, we propose to study the consequences of developmentally-restricted mutant htt expression on adult behavioral and neuropathological phenotypes by turning-on the expression of mutant htt at conception, and turning-off mutant htt expression at 1 month of age in HdhLacO-140Q/+; -actin LacIR-tg mice. Similarly, we will turn-on mutant htt expression at one month of age to study the role of compensation in HD pathogenesis. In Aim 2, we propose to determine if there are critical periods during the life of the mouse when normal htt expression must be maintained by turning-off normal htt expression at different ages in HdhLacO-3xFLAG-7Q/-; -actin LacIR-tg mice. Moreover, to model the therapeutic efficacy and safety of reducing overall Htt expression (Aim 3), we will combine both LacO-modified Hdh alleles in one mouse model (HdhLacO-140Q/LacO-3xFLAG-7Q; -actin LacIR-tg mice), and suppress both normal and mutant htt expression at 6 months or 1 year of age. PUBLIC HEALTH RELEVANCE: The development and application of new mouse models for Huntington's disease (HD) that can reversible turn-on or turn-off mutant and normal HD gene expression will enable us to explore developmental and compensatory mechanisms in HD pathogenesis, and will allow us to evaluate the efficacy and safety of potential therapeutic strategies for HD that are based on suppressing HD gene expression.

描述（由申请人提供）：亨廷顿氏病（HD）是一种主要的遗传疾病，是由Huntingtin（HTT）内编码一系列聚谷氨酰胺（PolyQ）的CAG三重态膨胀引起的，HUNTINGTIN（HTT）是HD基因的蛋白质产物。 HTT PolyQ伸展运动的扩展赋予了有害功能的有害收益，而同时丧失正常的HTT功能也会有助于发病机理。在HD和其他成人发作神经退行性疾病中，有证据表明发育过程中的功能障碍会导致后来的发病机理。或者，发育过程中作用的代偿机制可以延迟神经退行性的发作和运动/行为症状。我们的总体目标是使用新型的可抑制/诱导型敲门蛋白小鼠模型来探索发育表达和补偿在亨廷顿氏病进展中的作用，并确定必须保持正常的HTT表达时发育期间或成人不同年龄的关键时期。为此，我们正在开发敲蛋白小鼠模型，这些模型表达具有乳糖算子（LACO）序列的小鼠HD基因（HDH）的正常（7q）或突变体（140Q）版本，该基因（LACO）序列插入了启动子中。当这些HDHLACO等位基因与一个转基因一起表达时，编码了在小鼠中起作用的细菌乳糖阻遏物（LACIR）（HDHLACO-3XFLAG-7Q/ - ; -ACTIN LACIR-TG和HDHLACO-TG和HDHLACO-140Q/+; -ACTIR LACIR-TG MICE-CAN-CAN-CAN-OF-will-will-wilder-will-will-will-will-will-will-will-will-will-will-totepe-通过在小鼠的饮用水中施用或撤回异丙基 - D硫代乳糖苷（IPTG，乳糖类似物）。在AIM 1中，我们建议通过在概念上转动突变体HTT的表达，并在HDHLACO-140Q/+; HTHLACO-140Q/+; -Actin lacir-TG小鼠。同样，我们将在一个月大的时候开通突变体HTT表达，以研究补偿在HD发病机理中的作用。在AIM 2中，我们建议确定必须通过在HDHLACO-3XFLAG-7Q/ - 在不同年龄的不同年龄上关闭正常HTT表达时保持HTT表达时的关键时期。 -Actin lacir-TG小鼠。此外，为了建模降低HTT表达的治疗功效和安全性（AIM 3），我们将将两个LACO修饰的HDH等位基因结合在一个小鼠模型（HDHLACO-140Q/LACO-3XFLAG-7Q; -ATCIR-acTIR LACIR-TG MICE）中，并抑制正常和突变的HTT或1年。 公共卫生相关性：新老鼠模型的亨廷顿疾病（HD）的开发和应用可以逆转或关闭突变体和正常的HD基因表达，这将使我们能够探索HD发病机理中的发育和补偿机制，并使我们能够评估基于HD的疗效和基于Suppys Suppys Suppys Suppys Suppys hd gene Gene Gene Gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene的功效。