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A systematic study of the environmental etiology of autism spectrum disorder using high-throughput behavioral screening

使用高通量行为筛查系统研究自闭症谱系障碍的环境病因

基本信息

批准号：
10158025
负责人：
Yijie Geng
金额：
$ 8.83万
依托单位：
UNIVERSITY OF UTAH
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：
2020-05-04 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158025
关键词：
Affect Behavior Behavioral Binding Biochemical Biological Brain Chemicals DNA DNA Methylation DNA Modification Methylases DNA methyltransferase inhibition DSM-V Defect Development Developmental Gene Embryo Embryonic Development Environmental Risk Factor Epigenetic Process Etiology Exposure to Gene Expression Regulation Genetic Genetic Risk Genomics Goals Grant Human Investigation Lead Libraries Link Literature Longitudinal Studies Methods Mus Mutation Names National Institute of Environmental Health Sciences PHD Finger Pathway interactions Phenocopy Phenotype Play Protein Isoforms Regulation Ring Finger Domain Risk Rodent Model Role Social Behavior Social Development Stress Sum Symptoms System TOP2A gene Techniques Testing Tissues Topoisomerase II Topoisomerase II inhibition Topoisomerase-II Inhibitor Torsion Ubiquitin Zebrafish autism spectrum disorder base conditional knockout gain of function high throughput screening loss of function mouse model negative affect new therapeutic target overexpression prenatal exposure prevent repetitive behavior screening small molecule libraries social social communication impairment social deficits

项目摘要

PROJECT SUMMARY/ABSTRACT Identifying the causes of autism spectrum disorder has proven to be a significant challenge. Both genetic and environmental risk factors contribute to the development of autism. However, despite being estimated to account for 41% of autism risk, we know very little about the environmental risk factors of autism. Moreover, current systems that we are using to study how environmental factors influence autism risk, such as rodent models, are slow and laborious, and therefore not suitable for conducting large-scale systematic investigations. My long-term goal is to study the effect of environmental factors on the development of autism. Because social deficit is one of the 2 core symptoms of autism, I developed a high-throughput screening method to systematically search for chemicals that inhibit the development of social behavior in zebrafish. Using this system, I screened 1120 compounds, and identified a group of compounds - topoisomerase II (Top2) inhibitors - that effectively inhibited the normal development of social behavior in zebrafish. Prenatal exposure to the Top2 inhibitor ICRF-193 in mouse also induced behavioral defects related to the two core symptoms of autism. The main objective of this grant is to characterize the role of Top2 in the development of social behavior. Top2 is involved in gene regulation during brain development. Its two isoforms Top2a and Top2b are expressed in dividing and postmitotic tissues, respectively, during development, and modulate the expression of distinct sets of developmental genes. Top2 also regulates DNA methylation by binding to Uhrf1, a key adapter for Dnmt1. My preliminary results demonstrated that: 1) Top2a rather than Top2b is likely to be the biological target responsible for the social deficit phenotype; 2) chemical inhibition of Dnmts phenocopied Top2 inhibition and induced a similar social deficit phenotype in zebrafish; and 3) transient overexpression of Dnmt1 in zebrafish embryos rescued the social deficit phenotype induced by Top2 inhibitors. In addition, previous literatures have linked human mutations in TOP2A, TOP2B, and DNMT1 to increased autism risk. I thus propose the central hypothesis that Top2 plays a critical role in the development of social behavior through regulation of Dnmt1 and DNA methylation, and disruption of this pathway leads to deficits in sociality and other autism-related behaviors. To test this hypothesis, I propose to: 1) determine which Top2 isoform (Top2a or Top2b) is responsible for the social deficit phenotype induced by Top2 inhibition; 2) investigate the role of Dnmt1 and global DNA methylation in the development of social deficit following Top2 inhibition; and 3) To systematically discover environmental factors that affect the development of social behavior by screening the Tox21 library. Together, my proposed studies will have a broad impact on the field and may ultimately reveal novel therapeutic targets to prevent or treat autism.

项目概要/摘要事实证明，确定自闭症谱系障碍的原因是一项重大挑战。无论是遗传还是环境风险因素会导致自闭症的发生。然而，尽管估计占自闭症风险的41%，但我们对自闭症的环境风险因素知之甚少。而且，我们当前用于研究环境因素如何影响自闭症风险的系统，例如啮齿动物模型缓慢且费力，因此不适合进行大规模的系统研究。我的长期目标是研究环境因素对自闭症发展的影响。因为社交缺陷是自闭症的两个核心症状之一，我开发了一种高通量筛查方法来系统地寻找抑制斑马鱼社会行为发展的化学物质。使用这个系统中，我筛选了1120个化合物，鉴定出一组化合物——拓扑异构酶II（Top2）抑制剂 ——有效抑制了斑马鱼社会行为的正常发展。产前暴露于 Top2 抑制剂 ICRF-193 在小鼠体内也会诱导与自闭症的两个核心症状相关的行为缺陷。这笔资助的主要目的是描述 Top2 在社会行为发展中的作用。前2名参与大脑发育过程中的基因调控。它的两个亚型 Top2a 和 Top2b 表达为分别在发育过程中分裂和有丝分裂后组织，并调节不同组的表达的发育基因。 Top2 还通过与 Uhrf1（Dnmt1 的关键适配器）结合来调节 DNA 甲基化。我的初步结果表明：1）Top2a而不是Top2b可能是生物学目标造成社交缺陷表型； 2) Dnmts 表型 Top2 抑制的化学抑制和在斑马鱼中诱发类似的社交缺陷表型； 3) Dnmt1 在斑马鱼中瞬时过度表达胚胎挽救了 Top2 抑制剂诱导的社交缺陷表型。另外，之前的文献有 TOP2A、TOP2B 和 DNMT1 的人类突变与自闭症风险增加有关。因此，我提出了中心假设：Top2 在社会行为的发展中起着至关重要的作用通过调节 Dnmt1 和 DNA 甲基化，破坏该途径会导致社交缺陷以及其他与自闭症相关的行为。为了检验这个假设，我建议：1）确定哪种 Top2 同工型（Top2a 或 Top2b）负责 Top2 抑制引起的社交缺陷表型； 2）调查 Dnmt1 和整体 DNA 甲基化在 Top2 抑制后社交缺陷发展中的作用；和 3) 通过筛选系统地发现影响社会行为发展的环境因素 Tox21 库。总之，我提出的研究将对该领域产生广泛的影响，并最终可能揭示预防或治疗自闭症的新治疗靶点。