Genetic Strategies for Neurodevelopmental Research

神经发育研究的遗传策略

基本信息

批准号：
10319602
负责人：
David G Amaral
金额：
$ 74.26万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319602
关键词：
Affect Affective Age Animal Model Animals Attention Behavioral Biological Assay Biological Factors Biology Biomedical Research Biopsy Brain CRISPR/Cas technology California Characteristics Child Childhood Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Cost efficiency Data Development Disease Electroporation Embryo Embryo Transfer Etiology Fetus First Pregnancy Trimester Functional Magnetic Resonance Imaging Funding Generations Genes Genetic Genetic Research Genetically Modified Organisms Goals Growth Guide RNA Health Human Individual Infrastructure Institutes Intervention Leadership Live Birth Macaca mulatta Macrocephaly Measurement Medical Megalencephaly Methodology Microinjections Modeling Modification Molecular Monitor Monkeys Mothers Motor Mus Mutate Mutation Mutation Analysis Neonatal Neurobiology Neurodevelopmental Disorder Oocytes Phase Phenocopy Phenotype Positioning Attribute Pregnancy Primates Production Proteins RNA Reflex action Research Research Personnel Rest Rodent Rodent Model Route Sampling Series Social Behavior Stimulus Techniques Third Pregnancy Trimester Time United States Validation Variant Weight autism spectrum disorder chromatin remodeling clinically significant cost effective disability embryo cell embryo cryopreservation experience gene function genetic approach genetic manipulation implantation improved individuals with autism spectrum disorder interest loss of function loss of function mutation mouse model multimodality mutant nonhuman primate offspring preference programs social success

项目摘要

Autism Spectrum Disorder (ASD) affects 1-2% of children in the United States. The etiology(ies) and neurobiological underpinnings of autism remains unclear and hence targets for effective medical treatments are rare. While myriad genetic mouse models have been created, and many demonstrate some phenotypic features of autism, there is growing concern that rodent models may not be the best approach for creating phenocopies of childhood disorders, such as autism, that have cognitive and social disabilities as their core features. Over the last 5 years, through the use of techniques such as CRISPR/Cas9, there has been a revolution in genetically modifying organisms that can be applied to large species such as nonhuman primates (NHP). A first goal of this application is to develop a nonhuman primate model of ASD through loss of function modifications to the CHD8 gene. The gene encoding the chromatin remodeler CHD8 is among the most frequently mutated genes in individuals with ASD. The CHD8 form of autism is unique in being both highly penetrant and having a behavioral and neurobiological phenotype. Individuals with loss of function of this gene not only have autism but typically demonstrate macrocephaly/megalencephaly. We have selected this gene as a starting point because UC Davis Co-investigators on this application have been developing mouse models with Chd8 mutations and analysis of megalencephaly is a major focus of a recently funded Autism Center of Excellence at the MIND Institute. A second goal of the application is to build capacity and expertise in generating genetically modified nonhuman primate models of neurodevelopmental disorders. We argue that UC Davis, with its California National Primate Research Center that houses over 4000 rhesus monkeys, the Mouse Biology Program that has expertise in genetic manipulations leading to hundreds of clinically significant mouse models, and the MIND Institute which houses expertise on all facets of neurodevelopmental disorders research from genetics to clinical trials, is extraordinarily well-positioned to generate and comprehensively evaluate these animal models. We will establish a Leadership Group that will guide this program to successful development of valuable nonhuman primate models of neurodevelopmental disorders. For this initial phase of studies we propose 1) to implement strategies for gene editing of the nonhuman primate, validation of gene editing and efficient production of embryos for later implantation 2) to produce up to ten live rhesus monkeys with Chd8 loss of function mutations 3) to determine normal and abnormal trajectories of structural and functional brain development for rhesus monkeys with Chd8 loss of function mutations and 4) to carry out behavioral analyses of the genetically modified offspring. While the proximal goal of this application is to develop a valuable NHP model to facilitate understanding of the neurobiological underpinnings of autism, a long-term goal is to establish infrastructure to enable the generation of genetically modified monkeys for translational biomedical research more globally - which we believe to be in the national interest.

自闭症谱系障碍（ASD）影响美国1-2％的儿童。病因（IES）和自闭症的神经生物学基础尚不清楚，因此有效治疗的目标很少见。虽然已经创建了无数遗传小鼠模型，但许多人证明了某些表型自闭症的特征，人们越来越担心啮齿动物模型可能不是创建的最佳方法具有认知和社会残疾作为其核心的儿童疾病的表情，例如自闭症特征。在过去的5年中，通过使用CRISPR/CAS9等技术，已经有一个可以应用于非人类灵长类动物等大物种的基因修饰生物的革命（NHP）。该应用程序的第一个目标是通过丧失功能来开发ASD的非人类灵长类动物模型对CHD8基因的修改。编码染色质重塑的基因CHD8是最多的基因 ASD个体中经常突变的基因。自闭症的CHD8形式在高度方面是独一无二的渗透物，具有行为和神经生物学表型。该基因功能丧失的个体不仅有自闭症，而且通常表现出脑畸形/大脑。我们选择了这个基因一个起点，因为该应用程序上的UC Davis共同投资者正在开发鼠标模型有了CHD8突变和大脑分析，是最近资助的自闭症中心的主要重点心灵学院的卓越表现。该应用程序的第二个目标是建立能力和专业知识产生神经发育障碍的转基因非人类灵长类动物模型。我们争论加州大学戴维斯（UC Davis）及其加利福尼亚国家灵长类动物研究中心，该中心拥有4000多个恒河猴，小鼠生物学计划在遗传操作方面具有专业知识，导致数百种临床意义鼠标模型，以及在神经发育障碍的所有方面都拥有专业知识的思维学院从遗传学到临床试验的研究非常适合生成和全面地产生和全面评估这些动物模型。我们将建立一个领导小组，将指导该计划成功开发有价值的神经发育障碍的非人类灵长类动物模型。对于这个初始阶段我们建议的研究1）实施非人类灵长类动物的基因编辑策略，基因的验证编辑和有效的胚胎生产以供以后植入2）产生多达十个活恒河猴与CHD8功能突变的丧失3）确定结构和异常的结构和异常轨迹 CHD8功能突变丧失的恒河猴的功能性脑发育，4）基因修饰后代的行为分析。虽然此应用程序的近端目标是开发有价值的NHP模型，以促进对自闭症神经生物学基础的理解，一个长期目标是建立基础设施，以使产生转基因猴子的生成翻译生物医学研究在全球范围内更加全球 - 我们认为这符合国家利益。