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Development of a Novel Model for Tourettes Syndrome

抽动秽语综合症新模型的开发

基本信息

批准号：
8215517
负责人：
NICOLE CALAKOS
金额：
$ 15.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215517
关键词：
Acute Adult Affect Alleles Anabolism Animal Model Attention deficit hyperactivity disorder Behavior Behavioral Biology Brain C57BL/6 Mouse Clinical Code Comorbidity Constitution Corpus striatum structure Defect Development Disease ES Cell Line Enzymes Fathers First Degree Relative Future Gene Deletion Gene Proteins Gene-Modified Genes Genetic Genetic Models Genetic Predisposition to Disease Gilles de la Tourette syndrome Goals Heterozygote Histamine Histidine Decarboxylase Human Human Genetics Inheritance Patterns Inherited Knockout Mice Light Measures Mediating Messenger RNA Modeling Mouse Protein Movement Disorders Mus Mutant Strains Mice Mutation Nonsense Codon Nonsense Mutation Obsessive-Compulsive Disorder Partner in relationship Pathogenesis Patients Penetrance Phase Phenotype Physiology Population Preclinical Drug Evaluation Preclinical Testing Proteins Reagent Role Screening procedure Site Slice Specificity Symptoms Synaptic Transmission Testing Transgenic Organisms Triad Acrylic Resin Variant base behavior test disease mechanisms study drug development embryonic stem cell extracellular mouse genome mouse model mutant neurotransmission novel novel therapeutics offspring programs protein protein interaction recombinase transmission process

项目摘要

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. PUBLIC HEALTH RELEVANCE: The lack of animal models for Tourette Syndrome and its associated conditions of tics, obsessive compulsive disorder, and attention-deficit hyperactivity disorder present a substantial barrier to progress in identifying the underlying mechanisms for these conditions as well as for preclinical testing of candidate therapies. This proposal aims to develop a mouse model for Tourette Syndrome based on a human genetic etiology involving a nonsense mutation within the histidine decarboxylase gene. This mouse model will provide a previously unavailable reagent with human etiological relevance. To most faithfully replicate the human pathogenesis, the modified gene will be altered to encode the human protein, making this mouse model also uniquely suited for drug development and screening programs that target the human HDC protein.

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。公共卫生相关性：缺乏抽动秽语综合征及其相关病症的动物模型，强迫症和注意力缺陷多动障碍对识别这些病症的潜在机制以及候选疗法的临床前测试的进展构成了实质性障碍。该提案旨在基于涉及组氨酸脱羧酶基因内的无义突变的人类遗传病因学来开发抽动秽语综合征的小鼠模型。该小鼠模型将提供一种以前无法获得的具有人类病因学相关性的试剂。为了最忠实地复制人类发病机制，修饰的基因将被改变以编码人类蛋白质，使得这种小鼠模型也独特地适合于靶向人类HDC蛋白质的药物开发和筛选计划。