Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment
绘制神经发育过程中细胞分辨率的自闭症风险监管网络
基本信息
- 批准号:10008391
- 负责人:
- 金额:$ 15.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-18 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAffinityAnimal ModelBehavioral SymptomsBindingBiologicalBiological AssayBiological AvailabilityBiological ModelsBiological Response Modifier TherapyBiologyBiotinBrainCell modelCellsChildChild PsychiatryCollaborationsCongenital DisordersDNA-Binding ProteinsDataDevelopmentDiseaseDoctor of MedicineDoctor of PhilosophyEducationEmbryoEmploymentEngineeringEtiologyEvolutionExposure toExpression ProfilingFoundationsFutureGene ExpressionGenesGeneticGenetic DiseasesGenetic HeterogeneityGenetic studyGenomicsGoalsHumanImageImpairmentIndividualInvestigationK-Series Research Career ProgramsKnockout MiceKnowledgeLifeLigandsLigaseMachine LearningMapsMentorshipModelingMolecularMolecular GeneticsMusMutationNeurodevelopmental DisorderNeurologicNeuronsPathologyPathway AnalysisPathway interactionsProteinsPsychiatristPublic HealthRNAReporterReportingResearchResearch PersonnelResearch TrainingResolutionResourcesRiskRisk FactorsRoleSignal PathwaySiteStatistical ModelsSymptomsSystems AnalysisSystems BiologyTimeTissuesTraining ProgramsVariantautism spectrum disorderbasebiochipcareercareer developmentcell typechromatin immunoprecipitationchromatin remodelingdifferential expressiondisorder riskfetalfunctional genomicsgenetic architecturegenetic risk factorgenome-widehelicaseinnovationinsightlearning networkmathematical modelneocorticalnerve stem cellneurobehavioral disorderneurodevelopmentnovelnovel therapeuticsrisk variantsingle-cell RNA sequencingskillssmall moleculesocial communicationtargeted treatmenttherapeutic developmenttherapeutic targettooltranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Dr. Muhle is a practicing child psychiatrist with a strong track record of developing molecular and
genetic tools to elucidate the mechanism of disease. The long-term goal of this career development award is to
identify regulatory networks underlying autism spectrum disorder (ASD) through the integration of state-of-the-
art functional genomics, single cell transcriptomics, and systems biology analyses with precision-engineered
models of early brain development. She initiated this project during her time in the Adult and Child Psychiatry
Research Training Program at the Yale Child Study Center, with the mentorship of James Noonan, Ph.D. and
co-mentorship of Matthew State, M.D., Ph.D. With the guidance of Dr. Noonan, a world-wide leader in using
functional genomics to understand development and evolution, and the support of Dr. State, an undisputed
pioneer and leader in ASD genetics, Dr. Muhle developed expertise in regulatory genomics and the genetic
architecture of ASD. Her career goal is to become an independent investigator, examining the role of the ASD
risk gene Chromodomain Helicase DNA-binding Protein 8 (CHD8) in the development of ASD.
Her research goal is to determine the role of CHD8 and the impact of its loss on regulatory networks.
Our hypothesis is that CHD8 regulates ASD risk-associated networks in specific cell-types that become
dysregulated when CHD8 expression is altered. To address these questions, she successfully generated a
Chd8 constitutive knockout mouse and an Avi-tagged Chd8 mouse that she will use to identify Chd8-regulated
networks in specific cell-types at high cellular resolution. She also proposes a high-throughput small molecule
screen to explore potential upstream developmental signaling pathways that effect CHD8-regulated expression
networks. The following independent specific aims will address our hypothesis: 1) Determine cell-type specific
expression changes due to Chd8 haploinsufficiency in the developing cortex. 2) Map Chd8-bound cell-type
specific regulatory networks at high resolution in the cortex. 3) Identify bioactive modulators of CHD8
expression networks via high-throughput reporter assay. Our rationale is that by studying CHD8, a key
regulatory molecule that targets other ASD risk genes, we will expand our knowledge of other ASD risk genes
and identify CHD8-targeted regulatory networks in particular cell-types to further define the biology of ASD.
With the continued mentorship of Dr. Noonan and co-mentorship of Marina Picciotto, M.D., an expert in
animal models of neurobehavioral disorders, with collaboration of Thomas Fernandez, M.D., a child
psychiatrist with expertise in systems analyses of genetic risk factors, and Smita Krishnaswamy, Ph.D., a
computational biologist on the cutting-edge of statistical and mathematical modeling, Dr. Muhle will develop the
experimental and analytical skills necessary to fully utilize the model systems she has developed. Together
with the resources of the Yale Child Study Center and her career development goals, she will attain her career
goal to illuminate basic biological mechanisms underlying brain development and risk for ASD.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Rebecca Ann Muhle其他文献
Rebecca Ann Muhle的其他文献
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{{ truncateString('Rebecca Ann Muhle', 18)}}的其他基金
IMPACT OF LOSS OF THE AUTISM RISK GENE CHD8 ON EXPRESSION, EPIGENETICS AND CELLULAR FUNCTIONING OF THE DOPAMINERGIC SYSTEM
自闭症风险基因 CHD8 缺失对多巴胺能系统表达、表观遗传学和细胞功能的影响
- 批准号:
10660565 - 财政年份:2023
- 资助金额:
$ 15.41万 - 项目类别:
Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment
绘制神经发育过程中细胞分辨率的自闭症风险监管网络
- 批准号:
10464139 - 财政年份:2017
- 资助金额:
$ 15.41万 - 项目类别:
Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment
绘制神经发育过程中细胞分辨率的自闭症风险监管网络
- 批准号:
9431483 - 财政年份:2017
- 资助金额:
$ 15.41万 - 项目类别:
Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment
绘制神经发育过程中细胞分辨率的自闭症风险监管网络
- 批准号:
10006848 - 财政年份:2017
- 资助金额:
$ 15.41万 - 项目类别:
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