Cellular and Molecular Mechanisms of Behavioral Dysfunction in a Zebrafish Model of CHARGE Syndrome
电荷综合征斑马鱼模型行为障碍的细胞和分子机制
基本信息
- 批准号:10372659
- 负责人:
- 金额:$ 41.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-10 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:Acoustic StimulationAcousticsAffectAnxietyAreaAtlasesAttention deficit hyperactivity disorderAuditoryBehaviorBehavior TherapyBehavioralBehavioral MechanismsBehavioral SymptomsBrainBrain regionCHARGE syndromeCHD7 geneCRISPR/Cas technologyCellsChoanal AtresiaChromatin Remodeling FactorClutch SizeColobomaComputer softwareDNA BindingDataDefectDevelopmentDiseaseEarElementsEyeFertilizationFunctional disorderGenesGeneticGenetic DiseasesGenetic TranscriptionGenitalGenitaliaGenitourinary systemGenotypeGlutamatesGoalsHeartHeart AbnormalitiesHeterozygoteHuman GeneticsImageImpairmentInformal Social ControlIntellectual functioning disabilityLabelLarvaLightingLinkLive BirthLocationMeasuresMediatingMethodsMicroinjectionsMicroscopyModelingMolecularMolecular TargetMorphologyMutateNervous system structureNeurodevelopmental DisorderNeuronsObsessive-Compulsive DisorderOpticsPainPathway interactionsPatientsPatternPharmacologyPhotic StimulationPopulationProteinsProteomeProteomicsRegulationResearchResourcesRoleSamplingSensoryShapesSiteSleep DisordersStartle ReactionStereotypingStimulusStructureSystemTechniquesTherapeuticTissuesTransgenic OrganismsVisualWorkZebrafishauditory processingautism spectrum disorderbasebehavioral phenotypingbrain morphologycell typechromatin remodelingclinically relevantcommon symptomdriving behaviorhuman diseasein vivoin vivo calcium imagingin vivo imagingloss of function mutationmalformationmolecular dynamicsmorphometrymotor impairmentmutantneural circuitneurobehavioralneurodevelopmentneuronal circuitrynovelnovel diagnosticsnovel therapeutic interventionrelating to nervous systemresponsetranscriptometranscriptome sequencingtranscriptomicsvisual information
项目摘要
Project Summary
CHARGE syndrome is a rare, multi-system disorder that affects approximately 1 in 10,000 live births. The most
common symptoms include ocular coloboma, choanal atresia, heart defects, genital abnormalities, ear
malformations, and an array of neuro-behavioral difficulties. Sensory under- or over-load, motor impairments,
enhanced pain, sleep disorders, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder
(OCD), intellectual disability, anxiety, and autism are all frequently observed in CHARGE. Treatments for these
behavioral symptoms are limited, highlighting an area of critical need in understanding the mechanisms
underlying these defects in order to develop new therapeutic approaches. Two-thirds of CHARGE cases are
caused by loss-of-function mutations in chd7, which encodes a DNA-binding, ATP-dependent chromatin
remodeling protein. chd7 is highly expressed in the developing vertebrate brain and regulates transcription of
several key neurodevelopmental genes, but direct cellular and molecular links between chd7 function and
behavioral regulation have not been established. This project leverages the larval zebrafish model, which has
rapidly emerged as a powerful system for investigating the development and function of behavioral circuits as
well as human genetic disease. Using CRISPR/Cas9 we have established a chd7-null line and have
characterized several morphological and behavioral phenotypes reflective of CHARGE. In response to acoustic
stimuli, chd7 mutants perform normal short-latency startle responses (SLCs) but have impaired long-latency
escape responses (LLCs). Similarly, chd7 mutants respond normally to increases in illumination but are deficient
in responding to decreases in illumination. These deficits are independent of morphological defects in the eyes
and ears, indicating that chd7 likely regulates specific behavioral circuits in the brain. In Aim 1 we will
systematically interrogate the known circuit elements driving these behaviors using in vivo calcium imaging and
cell-specific rescue to locate the sites of chd7 action. We will then comprehensively define the brain regions that
are dependent on chd7 using whole-brain morphometry and activity analyses. In Aim 2 we will apply state-of-
the-art proteomic and transcriptomic approaches to identify molecular pathways that link chd7 with these
changes in brain structure and function. By analyzing samples from three developmental timepoints, we will also
define the temporal dynamics of these changes. Finally, we will use a systematic CRISPR/Cas9 approach to
validate the top proteomics- and transcriptomics-based chd7 targets in vivo by measuring brain development
and behavior in mutant larvae. Overall, the results of this work will establish direct links between chd7, its
molecular targets, and behavioral circuits. Furthermore, these aims will generate a powerful set of broadly useful
resources for interrogating the cellular and molecular bases of chd7-dependent neural development.
项目摘要
Charge综合征是一种罕见的多系统疾病,大约每10,000名活产儿中就有1名受到影响。最多的
常见症状包括眼部缺损、后鼻孔闭锁、心脏缺陷、生殖器畸形、耳朵
畸形和一系列神经行为障碍。感觉负荷不足或过载,运动障碍,
疼痛加剧、睡眠障碍、注意力缺陷多动障碍(ADHD)、强迫症
强迫症、智力障碍、焦虑和自闭症都是经常被观察到的。对这些疾病的治疗
行为症状是有限的,突出了理解机制的关键需要的领域
这些缺陷的潜在原因,以开发新的治疗方法。三分之二的指控案件是
由CHD7功能缺失突变引起,CHD7编码一种DNA结合的、依赖于ATP的染色质
重塑蛋白。CHD7在发育中的脊椎动物脑中高度表达,并调节
几个关键的神经发育基因,但CHD7功能和CHD7之间的直接细胞和分子联系
行为规范尚未建立。该项目利用了斑马鱼幼体模型,该模型具有
迅速崛起为研究行为电路的发展和功能的强大系统,如
以及人类遗传病。使用CRISPR/Cas9,我们已经建立了CHD7-NULL行,并且
表征了几种反映电荷的形态和行为表型。响应于声学
在刺激下,CHD7突变体执行正常的短潜伏期惊吓反应(SLC),但长潜伏期受损
逃逸反应(LLC)。同样,CHD7突变体对光照增加的反应正常,但存在缺陷
对照度的降低作出反应。这些缺陷与眼睛的形态缺陷无关。
和耳朵,这表明CHD7可能调节大脑中的特定行为回路。在目标1中,我们将
使用体内钙成像和系统地询问驱动这些行为的已知电路元件
细胞特异性抢救以定位CHD7的作用部位。然后我们将全面定义大脑区域,
依赖CHD7的全脑形态计量学和活动分析。在目标2中,我们将应用状态-
最先进的蛋白质组学和转录组学方法来确定将CHD7与这些基因联系起来的分子途径
大脑结构和功能的改变。通过分析来自三个发展时间点的样本,我们还将
定义这些变化的时间动态。最后,我们将使用系统的CRISPR/Cas9方法来
通过测量大脑发育来验证体内基于蛋白质组和转录组学的顶级CHD7靶点
以及突变幼虫的行为。总体而言,这项工作的结果将在CHD7、ITS
分子靶标和行为回路。此外,这些目标将产生一套强大的、广泛有用的
询问CHD7依赖神经发育的细胞和分子基础的资源。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent.
- DOI:10.1111/gbb.12839
- 发表时间:2023-06
- 期刊:
- 影响因子:0
- 作者:
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Kurt C. Marsden其他文献
Kurt C. Marsden的其他文献
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{{ truncateString('Kurt C. Marsden', 18)}}的其他基金
Molecular and Cellular Mechanisms of Acoustic Startle Threshold Regulation
声惊吓阈值调节的分子和细胞机制
- 批准号:
10360545 - 财政年份:2021
- 资助金额:
$ 41.12万 - 项目类别:
Molecular and Cellular Mechanisms of Acoustic Startle Threshold Regulation
声惊吓阈值调节的分子和细胞机制
- 批准号:
10211396 - 财政年份:2021
- 资助金额:
$ 41.12万 - 项目类别:
Molecular and Cellular Mechanisms of Acoustic Startle Threshold Regulation
声惊吓阈值调节的分子和细胞机制
- 批准号:
10599887 - 财政年份:2021
- 资助金额:
$ 41.12万 - 项目类别:
Genetic Analysis of Acoustic Startle Behavior and Circuits
声惊吓行为和电路的遗传分析
- 批准号:
8447646 - 财政年份:2012
- 资助金额:
$ 41.12万 - 项目类别:
Genetic Analysis of Acoustic Startle Behavior and Circuits
声惊吓行为和电路的遗传分析
- 批准号:
8254236 - 财政年份:2012
- 资助金额:
$ 41.12万 - 项目类别:
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