Genetic Strategies for Neurodevelopmental Research

神经发育研究的遗传策略

• 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
• 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

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。病因和 自闭症的神经生物学基础仍然不清楚，因此有效的医学治疗的目标 是罕见的尽管已经建立了无数的遗传小鼠模型，并且许多小鼠模型显示出一些表型特征， 自闭症的特征，越来越多的人担心啮齿动物模型可能不是创造自闭症的最佳方法。 以认知和社交障碍为核心的儿童期疾病，如自闭症的表型模仿 功能.在过去的5年里，通过使用CRISPR/Cas9等技术， 转基因生物的革命，可以应用于大型物种，如非人类灵长类动物 （NHP）。本申请的第一个目标是通过功能丧失开发ASD的非人灵长类动物模型 对CHD 8基因的修饰。编码染色质重塑蛋白CHD 8的基因是最重要的基因之一。 ASD患者中频繁发生突变的基因。CHD 8型自闭症的独特之处在于， 具有行为和神经生物学表型。该基因功能丧失的个体 不仅患有自闭症，而且典型地表现为大头畸形/巨脑畸形。我们选择这个基因作为 这是一个起点，因为加州大学戴维斯分校的合作研究人员一直在开发小鼠模型， 与Chd 8突变和巨脑畸形的分析是最近资助的自闭症中心的一个主要重点， 在MIND研究所的卓越。该应用程序的第二个目标是建立能力和专门知识， 产生神经发育障碍的遗传修饰的非人灵长类动物模型。我们认为 加州大学戴维斯分校及其加州国家灵长类动物研究中心拥有4000多只恒河猴， 小鼠生物学计划，具有遗传操作的专业知识，导致数百个临床意义 小鼠模型，以及拥有神经发育障碍各方面专业知识的MIND研究所 从遗传学到临床试验的研究，是非常有利的地位，产生和全面 评估这些动物模型。我们将建立一个领导小组，指导该计划取得成功 开发有价值的非人灵长类神经发育障碍模型。在这个初始阶段， 我们提出的研究1）实施非人灵长类动物的基因编辑策略， 编辑和有效生产胚胎以供后期植入2）生产多达10只活的恒河猴 3）以确定结构和功能的正常和异常轨迹， 具有Chd 8功能缺失突变的恒河猴的功能性脑发育，以及4）进行 转基因后代的行为分析。虽然该应用程序的近端目标是 开发一个有价值的NHP模型，以促进对自闭症神经生物学基础的理解， 长期目标是建立基础设施，使转基因猴子的产生， 转化生物医学研究更全球化-我们认为这符合国家利益。