Development of a Novel Model for Tourettes Syndrome

描述（由申请人提供）：妥瑞氏综合征（TS）及其相关疾病（抽搐、强迫症、ADHD）构成了巨大的社会负担，因为据估计，仅TS就影响了近1%的人群。在理解这些疾病的机制方面取得进展的一个关键障碍是缺乏与人类疾病病因相关的动物模型。我们建议利用最近发现的TS的遗传病因，涉及组氨酸脱羧酶基因内的无义突变，以克服这一障碍。在这项提案中，我们将创建，验证和行为表征一种新的小鼠模型TS。为了最忠实地复制基于蛋白质的病理生物学，因为它发生在人类中，我们将创建“人源化”小鼠模型，表达人类蛋白质代替内源性小鼠蛋白质。此外，因为这样的模型将表达人TS突变体蛋白，一旦验证，该小鼠模型将独特地适合于以常规小鼠敲入方法所不能提供的方式筛选新的治疗剂。

DESCRIPTION (provided by applicant): Tourette Syndrome (TS) and its associated conditions (tics, OCD, ADHD) constitute a substantial societal burden, as TS alone is estimated to affect nearly 1% of the population. A critical barrier to progress in understanding the mechanisms for these disorders is the lack of animal models with etiological relevance to the human condition. We propose to take advantage of the recent discovery of a genetic etiology for TS involving a nonsense mutation within the histidine decarboxylase gene to overcome this barrier. In this proposal we will create, validate and behaviorally characterize a novel mouse model for TS. To most faithfully replicate the protein-based pathobiology as it occurs in humans, we will create "humanized" mouse models that express the human protein in place of the endogenous mouse protein. Moreover, because such a model will express the human TS mutant protein, once validated, this mouse model will be uniquely suited for screening novel therapeutics in a way that is not afforded by conventional mouse knockin approaches.