Autism-specific mutation in DACT1: Impact on brain development in a mouse model

DACT1 中自闭症特异性突变：对小鼠模型大脑发育的影响

基本信息

批准号：
7638397
负责人：
Benjamin N.R. Cheyette
金额：
$ 19.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-08 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7638397
关键词：
Address Affect Affinity Amino Acids Animal Model Area Autistic Disorder Basic Science Behavior Behavior Disorders Binding Biochemical Biological Biological Models Brain Child Complex Development Diagnosis Dimerization Disease Electrophysiology (science)Engineering Family Funding Gene Mutation Generations Genetic Predisposition to Disease Goals Grant Hippocampus (Brain)Human In Vitro Individual Inhibitory Synapse Intention Knock-in Mouse Knockout Mice Laboratories Lead Link Methods Morphology Mutation National Institute of Mental Health Neurites Neurons Pathogenesis Phenotype Physiology Positioning Attribute Post-Translational Protein Processing Property Prosencephalon Proteins Psychiatrist Psychiatry Reading Research Research Personnel Role Scientist Signal Transduction Single Nucleotide Polymorphism Slice Societies System Tertiary Protein Structure Training United States Variant Vertebral column autism spectrum disorder base career cell type design genetic pedigree improved mouse model neurodevelopment novel postnatal protein function public health priorities public health relevance research study success synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): We have identified a novel single nucleotide polymorphism (SNP) in the DACT1 locus that alters an evolutionarily conserved amino acid in a conserved domain of the protein. We hypothesize that this SNP, which tracks with the diagnosis of autism in an affected family, alters protein function in developing neurons to cause the disease. We have developed a model system in which to study functions of the corresponding protein in early postnatal forebrain neurons, a cell type that is likely to be relevant to autism pathogenesis. This system uses a novel conditional knock-out mouse line generated in my laboratory together with established methods for studying the maturation of hippocampal neurons (HCNs) in culture. Our specific aims are to answer the following questions: 1. Does loss of Dact1 have developmental consequences in forebrain neurons? 2. Does the autism-variant Dact1 protein have different biochemical properties than the wild type Dact1 protein? 3. Do the wild type and autism-variant Dact1 proteins display functional differences during neural development? This is an exploratory grant to the National Institute of Mental Health to support the laboratory of a young investigator who is a psychiatrist trained as a basic scientist. Our goal is to rapidly exploit this opportunity to investigate functions of a wild type and an autism-linked variant Dact1 protein during neural development. It is hoped that this will lead to a major area of research in this laboratory that will contribute importantly to progress in the autism field. PUBLIC HEALTH RELEVANCE: Autism afflicts as many as 1 in 150 children in the United States and is a behavioral disorder with a high negative impact on individuals, their families, and our society. Understanding its biological basis in order to improve diagnosis and treatment are high priorities for public health. This project investigates a gene mutation discovered in a family with autism and how this leads biologically to the disease.

描述（由申请人提供）：我们已经在DACT1基因座中确定了一种新型的单核苷酸多态性（SNP），该多态性（SNP）改变了蛋白质保守域中进化保守的氨基酸。我们假设该SNP跟踪受影响家庭中自闭症的诊断，可以改变蛋白质在发育神经元引起疾病中的功能。我们已经开发了一个模型系统，在该模型系统中，在早期产后前脑神经元中研究相应蛋白质的功能，这种细胞类型可能与自闭症的发病机理有关。该系统使用在我的实验室中产生的新型有条件敲除小鼠系，以及既定的方法来研究培养物中海马神经元（HCN）的成熟。我们的具体目的是回答以下问题：1。DACT1的损失是否对前脑神经元有发育后果？ 2。自闭症变异的DACT1蛋白是否具有与野生型Dact1蛋白不同的生化特性？ 3。野生类型和自闭症变异的DACT1蛋白是否在神经发育过程中显示出功能差异？这是美国国家心理健康研究所的探索性赠款，以支持一位受过基础科学家的精神病医生的年轻研究者的实验室。我们的目标是迅速利用这一机会来研究神经发育过程中野生型和自闭症变体DACT1蛋白的功能。希望这将导致该实验室的主要研究领域，这将为自闭症领域的进步做出重要贡献。公共卫生相关性：在美国，自闭症患有多达150名儿童的150名儿童，是一种行为障碍，对个人，家人和我们的社会产生了很大的负面影响。了解其生物学基础以改善诊断和治疗是公共卫生的高度优先事项。该项目调查了一个自闭症家庭中发现的基因突变，以及这如何在生物学上导致该疾病。