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）：Tourette综合征（TS）及其相关条件（TICS，OCD，ADHD）构成了巨大的社会负担，因为仅TS就估计会影响近1％的人口。了解这些疾病机制的进展的关键障碍是缺乏与人类状况具有病因相关的动物模型。我们建议利用最近发现的遗传病因，用于TS，涉及组氨酸脱羧酶基因内的废话突变以克服这一障碍。在此提案中，我们将创建，验证和行为表征用于TS的新型小鼠模型。为了最忠实地复制人类中基于蛋白质的病原体学，我们将创建“人性化”小鼠模型，以代替内源性小鼠蛋白来表达人蛋白。此外，由于这样的模型将表达人类TS突变蛋白（一旦得到验证），因此该小鼠模型将非常适合以常规小鼠敲除方法无法提供的方式筛选新型疗法。公共卫生相关性：缺乏图雷特综合症的动物模型及其相关的抽动条件，强迫症和注意力缺陷多动障碍在识别这些疾病的基本机制以及临床前测试的临床前测试方面具有实质性的障碍。候选疗法。该提案旨在基于人类遗传病因，涉及组氨酸脱羧酶基因中的胡说八道突变，为图雷氏综合征开发小鼠模型。该小鼠模型将提供具有人类病因相关性的先前不可用的试剂。为了最忠实地复制人类的发病机理，将改变修饰的基因以编码人类蛋白质，使该小鼠模型也非常适合针对人类HDC蛋白的药物开发和筛选程序。