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High-throughput functional analysis of autism risk genes

自闭症风险基因的高通量功能分析

基本信息

批准号：
10319985
负责人：
ELLEN J HOFFMAN
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319985
关键词：
Behavior Behavioral Biological Biological Assay Biology Brain Brain imaging CNTNAP1 gene CRISPR/Cas technology Critical Pathways Development Embryo Exposure to Fertilization Functional disorder Gene Cluster Genes Glutamates Goals Hour Image Knowledge Light Maps Morphology Neural Pathways Neurons Outcomes Research Pathway interactions Pharmacological Treatment Pharmacology Pharmacotherapy Phenotype Population Prevalence Process Research Rodent Role Sensory Stimulus Susceptibility Gene System Testing Time Transcriptional Regulation Visual Visualization Zebrafish autism spectrum disorder base behavioral pharmacology behavioral phenotyping brain morphology cell type estrogenic exome sequencing gene discovery gene function genetic manipulation glutamatergic signaling improved in vivo in vivo two-photon imaging innovation insight mutant neural circuit neuromechanism novel novel strategies regional difference relating to nervous system response risk variant small molecule small molecule libraries spatiotemporal synaptic function two-photon

项目摘要

The central objective of this research is to elucidate the function of genes that are strongly associated with autism spectrum disorders (ASD) in fundamental processes of vertebrate brain development. While whole-exome sequencing has led to a growing list of “high confidence” ASD (hcASD) risk genes, which are beginning to converge on common pathways, our understanding of the mechanisms by which hcASD gene disruption alters the development of specific cell types and neural circuits, resulting in behavioral dysfunction, remains limited. The long-term goal of this research is to illuminate the basic biological mechanisms underlying ASD, which will provide a much-needed avenue for the discovery of targeted pharmacological treatments. Here, we will capitalize on the unique advantages of zebrafish as an in vivo, biologically relevant system for the rapid functional analysis of multiple hcASD genes in parallel, including: (i) the ability to directly visualize basic neurodevelopmental processes and neural activity in a whole vertebrate brain through transparent embryos; (ii) large progenies, which are ideal for conducting high-throughput in vivo screens to identify small molecule suppressors of behavioral phenotypes; and (iii) ease of genetic manipulation, such that we have already generated zebrafish mutants in 10 top hcASD genes, which we will analyze in the present study. Our central hypothesis is that zebrafish mutants of hcASD genes will display quantifiable morphological, simple behavioral, and circuit-level phenotypes that will converge on common pathways, providing new insights into the roles of these genes in the developing vertebrate brain. This hypothesis is based on evidence from our study of zebrafish mutants of the ASD risk gene, CNTNAP2, which revealed dysregulation of GABAergic and glutamatergic signaling and identified a novel pharmacological suppressor of an ASD gene-associated mutant behavioral phenotype. To test this hypothesis, we will pursue the following aims: 1) Identify quantifiable brain phenotypes across 10 hcASD mutants using light-sheet imaging and automated deep phenotyping of CNS- specific markers; 2) Conduct high-throughput pharmaco-behavioral profiling of hcASD mutants using a novel, automated visual-startle assay and perform small molecule screens to identify suppressors of mutant startle phenotypes; and 3) Characterize neural circuit deficits underlying altered sensory processing behaviors in hcASD mutants and identify the circuit-level mechanisms of pharmacological suppressors using whole-brain in vivo two-photon imaging. This approach is highly innovative and is the first to analyze the function of multiple hcASD genes in parallel at the structural, behavioral, and circuit levels, allowing us to progress rapidly from risk gene discovery to the elucidation of convergent pathways with relevance to ASD. Therefore, we expect that this research will lead to critical advances in our understanding of the basic biology of ASD and provide a path forward in the discovery of mechanism-based pharmacological treatments.

本研究的中心目标是阐明与糖尿病密切相关的基因的功能

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

DOI：
10.1016/j.celrep.2023.112243
发表时间：
2023-03-28
期刊：
Cell reports
影响因子：
8.8
作者：
通讯作者：

PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets.

DOI：
10.1016/j.tins.2021.08.007
发表时间：
2021-12
期刊：
Trends in neurosciences
影响因子：
15.9
作者：
DeSpenza T Jr;Carlson M;Panchagnula S;Robert S;Duy PQ;Mermin-Bunnell N;Reeves BC;Kundishora A;Elsamadicy AA;Smith H;Ocken J;Alper SL;Jin SC;Hoffman EJ;Kahle KT
通讯作者：
Kahle KT

Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future.

DOI：
10.3389/fnmol.2018.00294
发表时间：
2018
期刊：
Frontiers in molecular neuroscience
影响因子：
4.8
作者：
Sakai C;Ijaz S;Hoffman EJ
通讯作者：
Hoffman EJ

Brain Registration and Evaluation for Zebrafish (BREEZE)-mapping: A pipeline for whole-brain structural and activity analyses.

DOI：
10.1016/j.xpro.2023.102647
发表时间：
2023-12-15
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Jin, David S.;Neelakantan, Uma;Lacadie, Cheryl M.;Chen, Tianying;Rooney, Brendan;Liu, Yunqing;Wu, Weimiao;Wang, Zuoheng;Papademetris, Xenophon;Hoffman, Ellen J.
通讯作者：
Hoffman, Ellen J.

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder.