High-throughput functional analysis of autism risk genes
High-throughput functional analysis of autism risk genes
批准号:
10319985
负责人:
ELLEN J HOFFMAN
金额:
$41.88万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-03-01 至 2023-12-31
关键词:
BehaviorBehavioralBiologicalBiological AssayBiologyBrainBrain imagingCNTNAP1 geneCRISPR/Cas technologyCritical PathwaysDevelopmentEmbryoExposure toFertilizationFunctional disorderGene ClusterGenesGlutamatesGoalsHourImageKnowledgeLightMapsMorphologyNeural PathwaysNeuronsOutcomes ResearchPathway interactionsPharmacological TreatmentPharmacologyPharmacotherapyPhenotypePopulationPrevalenceProcessResearchRodentRoleSensoryStimulusSusceptibility GeneSystemTestingTimeTranscriptional RegulationVisualVisualizationZebrafishautism spectrum disorderbasebehavioral pharmacologybehavioral phenotypingbrain morphologycell typeestrogenicexome sequencinggene discoverygene functiongenetic manipulationglutamatergic signalingimprovedin vivoin vivo two-photon imaginginnovationinsightmutantneural circuitneuromechanismnovelnovel strategiesregional differencerelating to nervous systemresponserisk variantsmall moleculesmall molecule librariesspatiotemporalsynaptic functiontwo-photon
中文摘要
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
英文摘要
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.
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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:
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
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
DOI:
10.1016/j.xpro.2023.102647
发表时间:
2023-12-15
期刊:
STAR PROTOCOLS
影响因子:
--
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.
DOI:
10.3389/fpsyt.2021.716673
发表时间:
2021
期刊:
Frontiers in psychiatry
影响因子:
4.7
作者:
[Enriquez KD, Gupta AR, Hoffman EJ]
通讯作者:
Hoffman EJ
Investigating the Translatome in Genetic Models of Autism
-
批准号:10649109
-
项目类别:
-
资助金额:$25.02万
-
财政年份:2023
-
负责人:ELLEN J HOFFMAN
-
依托单位:
Functional Analysis of Rare Variants in Genes Associated with Autism
-
批准号:8595337
-
项目类别:
-
资助金额:$14.66万
-
财政年份:2012
-
负责人:ELLEN J HOFFMAN
-
依托单位:
Functional Analysis of Rare Variants in Genes Associated with Autism
-
批准号:8404053
-
项目类别:
-
资助金额:$14.66万
-
财政年份:2012
-
负责人:ELLEN J HOFFMAN
-
依托单位:
Functional Analysis of Rare Variants in Genes Associated with Autism
-
批准号:8223931
-
项目类别:
-
资助金额:$14.66万
-
财政年份:2012
-
负责人:ELLEN J HOFFMAN
-
依托单位:
Functional Analysis of Rare Variants in Genes Associated with Autism
-
批准号:8788299
-
项目类别:
-
资助金额:$14.79万
-
财政年份:2012
-
负责人:ELLEN J HOFFMAN
-
依托单位:
国内基金
海外基金
Behavioral Insights on Cooperation in Social Dilemmas
-
批准号:--
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项目类别:外国优秀青年学者研究基金项目
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资助金额:--
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批准年份:2024
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负责人:LIEN,Jaimie Wei-Hung
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依托单位: