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：
8743424
负责人：
NICOLE CALAKOS
金额：
$ 23.55万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743424
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 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 screening 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.

描述（由申请人提供）：抽动秽语综合症 (TS) 及其相关病症（抽动症、强迫症、多动症）构成了巨大的社会负担，因为据估计仅抽动秽语综合症就影响了近 1% 的人口。理解这些疾病机制的一个关键障碍是缺乏与人类状况具有病因学相关性的动物模型。我们建议利用最近发现的 TS 遗传病因（涉及组氨酸脱羧酶基因内的无义突变）来克服这一障碍。在本提案中，我们将创建、验证并表征一种新型 TS 小鼠模型。为了最忠实地复制人类中基于蛋白质的病理学，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，由于这种模型将表达人类 TS 突变蛋白，一旦经过验证，该小鼠模型将特别适合以传统小鼠敲入方法无法提供的方式筛选新疗法。