Stable Zebrafish Models of Autism Spectrum Disorder

自闭症谱系障碍的稳定斑马鱼模型

• 批准号: 8684696
• 负责人: Julia Eve Dallman
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684696
• 关键词: Address; Affect; Age; American Psychiatric Association; Animal Model; Ankyrin Repeat; Basic Science; Behavior; Behavioral; Biological Assay; Brain; Characteristics; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Complex; Data; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Disease; Disease model; Embryo; Embryonic Development; Environmental Risk Factor; Etiology; Gene Mutation; Generations; Genes; Genetic; Genetic Heterogeneity; Genome; Goals; Human; Individual; Knock-out; Knowledge; Link; Mammals; Mission; Modeling; Motor; Mutation; Nervous system structure; Neuroanatomy; Neurons; Outcome; Phenotype; Physiology; Play; Preclinical Drug Evaluation; Prevalence; Process; Public Health; Research; Research Priority; Research Proposals; Role; Saints; Seizures; Signal Transduction; Social Behavior; Social Interaction; Staging; Stereotyping; Synapses; System; Technology; Testing; Therapeutic; United States; Work; Zebrafish; autism spectrum disorder; base; cost; drug use screening; endophenotype; follow-up; gamma-Aminobutyric Acid; in vivo; interest; knock-down; mutant; neural circuit; public health relevance; ras GTPase-Activating Proteins; research study; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) are currently estimated to impact 1-2.6% of children world-wide, representing a steep rise in ASD prevalence with annual costs to the United States alone calculated at $126 billion (2012). Because known therapies are less effective with increasing age of diagnosis, addressing outstanding questions about ASD etiology is a research priority. In the more common mammalian models however, embryonic stages are inaccessible therefore embryogenesis presents a major gap in our understanding of ASD etiology. To address this gap, we propose to generate zebrafish ASD models to focus explicitly on functional consequences in embryos of mutations known to cause ASD. Rather than investigate social behaviors typically used to define ASD, we focus on internal phenotypes (endophenotypes) of neuroanatomy and physiology. Following this strategy, our preliminary data from morpholino knockdown experiments demonstrate common phenotypes when either of two distinct ASD-linked genes, SHANK3 and SYNGAP1, is knocked down in zebrafish. Common phenotypes include developmental delay and seizure-like behaviors. These seizure-like behaviors are likely explained by dramatic reductions in the numbers of inhibitory GABAergic neurons in both morphant models. Developmental delay, seizures, and reduced markers of GABAergic signaling are also characteristic of individuals with ASD. To follow up on these preliminary studies we propose to generate stable gene knock-outs of zebrafish shank3 and syngap1. By creating and analyzing stable mutant lines with respect to the development of GABAergic brain circuits, our goal is to determine the developmental mechanisms that underlie GABA deficits. In the long-term, these zebrafish ASD models can also serve as the basis for the discovery of therapeutic targets and environmental risk factors.

描述（由申请人提供）：目前估计自闭症谱系障碍 (ASD) 影响着全世界 1-2.6% 的儿童，这表明自闭症谱系障碍患病率急剧上升，仅美国一年的费用就高达 1,260 亿美元（2012 年）。由于随着诊断年龄的增加，已知的治疗方法效果较差，因此解决 ASD 病因学的突出问题是研究的重点。然而，在更常见的哺乳动物模型中，胚胎阶段是无法进入的，因此胚胎发生在我们对自闭症谱系障碍病因学的理解中存在重大差距。为了解决这一差距，我们建议生成斑马鱼 ASD 模型，以明确关注已知导致 ASD 的突变对胚胎的功能影响。我们不研究通常用于定义 ASD 的社会行为，而是关注神经解剖学和生理学的内部表型（内表型）。按照这一策略，我们来自吗啉代敲低实验的初步数据证明了当两个不同的 ASD 相关基因 SHANK3 和 SYNGAP1 中的任何一个在斑马鱼中被敲低时，都会出现常见的表型。常见的表型包括发育迟缓和癫痫样行为。这些类似癫痫发作的行为可能是由于两种 morphant 模型中抑制性 GABA 能神经元数量的急剧减少所致。发育迟缓、癫痫发作和 GABA 信号标记减少也是 ASD 个体的特征。为了跟进这些初步研究，我们建议对斑马鱼 shank3 和 syngap1 进行稳定的基因敲除。通过创建和分析与 GABA 能脑回路发育有关的稳定突变系，我们的目标是确定 GABA 缺陷背后的发育机制。从长远来看，这些斑马鱼 ASD 模型还可以作为发现治疗靶点和环境风险因素的基础。