A vertebrate model of viral and hereditary microcephaly
病毒和遗传性小头畸形的脊椎动物模型
基本信息
- 批准号:10576107
- 负责人:
- 金额:$ 15.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-07 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnatomyAnimal ModelBiological AssayBiological ModelsBrainBrain DiseasesBrain regionCRISPR/Cas technologyCell PolarityChemical ExposureChemicalsDefectDevelopmentDiseaseDissectionDrosophila genusEmbryoEmbryonic DevelopmentEtiologyEyeFoundationsFutureGene MutationGene Transfer TechniquesGenesGoalsGrowthHeadHumanImmunofluorescence MicroscopyInfectionInheritedIntellectual functioning disabilityKnowledgeLeadLengthMeasurementMeasuresMicrocephalyModelingMolecularMorphologyMutateMutationNonstructural ProteinPathogenicityPathway interactionsPhenotypeProteinsPublishingSpecificityStructureStudy modelsSyndromeSystemTestingTransgenic OrganismsVariantVertebratesViralVirusVirus DiseasesWorkZebrafishZika Virusalcohol exposurebehavioral studybrain sizecDNA Expressioncell typeexperimental studyflygenome editinghigh throughput screeninghuman diseasein uteroin vivoinhibitornervous system disorderparalogous genepathogenscreeningstem cellstool
项目摘要
PROJECT SUMMARY/ABSTRACT
Microcephaly, in which head and brain development are severely inhibited, can result in extreme intellectual
disability. Microcephaly has many different causes, including gene mutation, pathogen infection and chemical
exposure. While the causes of microcephaly may be broad, there may be shared molecular mechanisms
involved. Recently published results show how Zika virus non-structural protein 4A (NS4A) inhibits brain
development in fruit flies by inhibiting the same ANKLE2 protein whose function is disrupted by gene mutation
in a hereditary form of microcephaly. This suggests that there may be key similarities in the molecular
mechanisms contributing to a viral and hereditary form of microcephaly. Studying these molecular similarities in
vertebrate models is essential to understanding disease in humans since vertebrates have different brain
structure and genes that regulate brain development. However, the tools to study this, namely a strong vertebrate
model system, do not exist.
The primary goal of the proposed project is to fill these major gaps in knowledge by developing a vertebrate
model of viral and hereditary microcephaly acting through the ANKLE2 pathway. For the hereditary model,
ankle2 will be mutated using CRISPR/Cas9 genome editing. For the viral model, Zika virus NS4A protein will be
expressed using Tol2 transgenesis. Defects in development, including various externally measured morphology
metrics, brain size, structure and cellular defects in proliferation and survival will be assayed using anatomical
measurement and immunofluorescence microscopy. When completed, this new model system will lay the
foundation for a molecular and cellular level understanding of ANKLE2 function during vertebrate brain
development and how it is disrupted by gene mutation and viral infection. In the long-term, it will enable high-
throughput screening of chemical sensitizers and inhibitors of microcephaly, allow the exploration vertebrate-
specific mechanisms of brain development in vivo, and behavioral studies.
项目摘要/摘要
头小畸形,头部和大脑发育受到严重抑制,可导致极端的智力障碍。
残疾。小头畸形有许多不同的原因,包括基因突变,病原体感染和化学
exposure.虽然小头畸形的原因可能很广泛,但可能有共同的分子机制
涉案最近发表的结果显示寨卡病毒非结构蛋白4A(NS 4A)如何抑制大脑
通过抑制相同的ANKLE 2蛋白(其功能被基因突变破坏)在果蝇中的发育
遗传性小头畸形这表明分子中可能存在关键相似之处
导致病毒性和遗传性小头畸形的机制。研究这些分子相似性,
脊椎动物模型对于理解人类疾病是必不可少的,因为脊椎动物具有不同的大脑
调节大脑发育的结构和基因。然而,研究这一点的工具,即强壮的脊椎动物,
模型系统不存在。
该项目的主要目标是通过开发一种脊椎动物来填补这些主要的知识空白
通过ANKLE 2途径起作用的病毒性和遗传性小头畸形模型。对于遗传模型,
踝2将使用CRISPR/Cas9基因组编辑进行突变。对于病毒模型,寨卡病毒NS 4A蛋白将被
使用Tol 2转基因表达。显影缺陷,包括各种外部测量形态
将使用解剖学方法测定增殖和存活中的指标、脑大小、结构和细胞缺陷。
测量和免疫荧光显微术。完成后,这个新的模型系统将奠定
为在脊椎动物脑中理解ANKLE 2功能的分子和细胞水平奠定基础
基因突变和病毒感染如何破坏它。从长远来看,它将使高-
通过筛选化学致敏剂和小头畸形抑制剂,可以探索脊椎动物-
体内大脑发育的具体机制和行为研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Priya Shirish Shah其他文献
Priya Shirish Shah的其他文献
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{{ truncateString('Priya Shirish Shah', 18)}}的其他基金
Molecular mechanisms linking viral replication and neuropathogenesis
连接病毒复制和神经发病机制的分子机制
- 批准号:
10660340 - 财政年份:2023
- 资助金额:
$ 15.99万 - 项目类别:
Molecular mechanisms linking viral replication and neuropathogenesis
连接病毒复制和神经发病机制的分子机制
- 批准号:
10673233 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
Conserved molecular mechanisms of replication for mosquito-borne flaviviruses
蚊媒黄病毒复制的保守分子机制
- 批准号:
10431689 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
Conserved molecular mechanisms of replication for mosquito-borne flaviviruses
蚊媒黄病毒复制的保守分子机制
- 批准号:
10577854 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
Quantitative mapping of interactions between dengue virus and its hosts
登革热病毒与其宿主之间相互作用的定量图谱
- 批准号:
8918261 - 财政年份:2015
- 资助金额:
$ 15.99万 - 项目类别:
Quantitative mapping of interactions between dengue virus and its hosts
登革热病毒与其宿主之间相互作用的定量图谱
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8783961 - 财政年份:2015
- 资助金额:
$ 15.99万 - 项目类别:
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