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Functional Analysis of Rare Variants in Genes Associated with Autism

自闭症相关基因罕见变异的功能分析

基本信息

批准号：
8788299
负责人：
ELLEN J HOFFMAN
金额：
$ 14.79万
依托单位：
YALE 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：
2012-01-03 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788299
关键词：
Acoustics Adult Architecture Autistic Disorder Axon Behavior Behavior assessment Behavioral Binding Biological Biological Assay Biological Models Biological Process Biology Cell Adhesion Molecules Child Child Development Chromosomes DNA Structure Data Development Developmental Biology Disease Doctor of Philosophy Embryo Emerging Technologies Fertilization Fishes Frameshift Mutation Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic study Germ-Line Mutation Goals Hour Human Genetics Imagery Immigration Impairment Individual K-Series Research Career Programs Knock-out Knowledge Laboratories Language Larva Lead Maps Medicine Mental disorders Mentors Methods Modeling Molecular Mutation Neural Cell Adhesion Molecules Neuraxis Neurobiology Neurons Neurosciences Orthologous Gene Outcomes Research Pathway interactions Pattern Phenotype Prevalence Process Proteins Psychiatrist Public Health Research Research Personnel Resources Risk Role Social Interaction Susceptibility Gene Synapses System Testing Variant Zebrafish Zinc Fingers autism spectrum disorder base behavior test career contactin disorder risk endonuclease gene discovery gene function genetic manipulation genetic variant genome-wide analysis human CNTNAP1 protein in vivo innovation insight loss of function migration nervous system development neural circuit neurodevelopment new therapeutic target novel nuclease prepulse inhibition rare variant response risk variant small molecule social tool zebrafish development

项目摘要

The goal of this career development award is to integrate the genetics of autism spectrum disorders (ASD), developmental neuroscience, and the functional analysis of rare variants, in order to advance our understanding of the basic biological mechanisms underlying ASD. Dr. Hoffman is a board certified, practicing child psychiatrist, who is currently pursuing her PhD in Investigative Medicine in the laboratory of Matthew State, MD, PhD, at the Yale Child Study Center. Her career goal is to become an independent investigator with dual expertise in the genetics of child psychiatric disorders and the neurobiology of vertebrate systems. In this application, she proposes to utilize zebrafish as a novel translational tool that will leverage findings from human genetic studies as a means of advancing our knowledge of the pathophysiology of ASD. Dr. Hoffman will gain this expertise through the combined guidance of her primary mentor, Dr. State, a leader in ASD genetics, and co-mentor, Antonio Giraldez, PhD, an expert in zebrafish development, which will promote the establishment of this innovative approach to investigating the role of ASD susceptibility genes in neural circuit formation. The objective of this research is to elaborate basic mechanisms of ASD by investigating the function of the ASD risk gene, Contactin Associated Protein-2 (CNTNAP2) in neural development, and to determine how sequence variants in this gene identified in individuals with ASD disrupt its function. Using the emerging technology of zinc finger nucleases, which have superior accuracy over morpholinos, Dr. Hoffman induced targeted germline mutations in the two zebrafish CNTNAP2 genes, CNTNAP2a and 2b. To our knowledge, this is the first zebrafish knockout of an ASD risk gene generated by this method. Our hypothesis is that CNTNAP2a/2b double knockouts will display reproducible morphological and/or behavioral phenotypes that will yield important insights into the function of CNTNAP2 in neural development. This hypothesis will be tested by pursuing these aims: 1) Generate double knockouts of the two zebrafish CNTNAP2 genes by crossing fish carrying germline mutations; 2) Identify quantifiable morphological and/or behavioral phenotypes in CNTNAP2 double knockouts; and 3) Characterize the ability of the human CNTNAP2 gene with rare sequence variants found in individuals with ASD to reverse the phenotypes. Our rationale for this approach is that the development of an in vivo system to rapidly assess the functional consequences of rare genetic variants is the crucial next step in understanding the biology of ASD. Dr. Hoffman has assembled an outstanding team of mentors and collaborators, including pioneers in zebrafish neural circuit analysis and behavioral phenotyping, as this system is anticipated to provide unique insights into the role of CNTNAP2 in the neural circuitry underlying simple behaviors. The extensive resources of the Yale Child Study Center, together with her formal plan for didactics in neuroscience and developmental biology, will further support Dr. Hoffman¿s goal of elucidating the molecular and cellular mechanisms of ASD.

这一职业发展奖项的目标是整合自闭症谱系障碍（ASD）的遗传学、发育神经科学和罕见变异的功能分析，以促进我们对ASD基础生物学机制的理解。霍夫曼博士是一名董事会认证的执业儿童精神病学家，目前正在耶鲁儿童研究中心的马修州立医学博士实验室攻读调查医学博士学位。她的职业目标是成为一名具有儿童精神疾病遗传学和脊椎动物系统神经生物学双重专业知识的独立研究者。在这个