Highly specific, temporally controllable mouse genetic tools for investigating in
用于研究的高度特异性、时间可控的小鼠遗传工具
基本信息
- 批准号:8700557
- 负责人:
- 金额:$ 23.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-15 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdultAnimal ModelAstrocytesBiologyBrainBrain NeoplasmsCSPG4 geneCell physiologyCellsConsultDevelopmentDiseaseDoxycyclineEnsureFoundationsFutureGeneticGenomicsGluesGrantIndividualKnock-in MouseLearningMosaicismMusNatureNeuraxisNeurogliaNeuronsNeurosciencesOperonPlayPreparationRNAResearchRoleSideSpecificitySystemTetanus Helper PeptideTherapeutic InterventionTransgenesWorkbasecell typecellular targetingcognitive functiondesignembryonic stem cellexperiencein vivoinsightnervous system disordernoveloligodendrocyte precursorprecursor cellpublic health relevanceresearch studyscaffoldsuccesstooltranscriptomicstransgene expressiontreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Glial cells form intimate contact with neurons and help orchestrate brain wiring during development and facilitate neuronal functions in adulthood. Therefore, it is important to elucidate glial functions in vivo. However, highly specific and adaptable mouse lines for studying two major glial cell types, mature astrocytes and NG2 cells are still lacking. Here we propose to create mouse genetic tools that would allow one to probe into the function of these two types of glial cells in a temporally controllable fashion. The proposed Tet-OFF binary system consists of two groups of mice: 1) driver lines that express tTA in specific types of glial cells; 2) effector lines that express transgenes for cell ablation or transcriptomic profiling under the control of Tet Operon (TetO). The system would allow one to pick and choose individual driver and effector lines to study a specific problem in glial biology. When combined with existing Cre lines, intersectional genetics can provide unprecedented cell type-specificity to analyze glial functions in vivo. Although apparently straightforward, problems of leakiness, variegation/mosaicism, and silencing of transgene expression could derail such efforts. With careful preparation, our lab is now ready to take on this challenge. With our extensive experience with ES cell-based knock-in strategy gained from creating and optimizing a mouse genetic mosaic system, we will use carefully designed targeting strategies to ensure the faithfulness and completeness of transgene expression. As importantly, we have broadly consulted with leaders in the field of glial biology and mouse genetics, and will target these transgenes into the most promising genomic loci for faithful and specific transgene expression. We believe that genetic tools described in this grant will have a broad impact on studying the roles of glial cells for normal functions and diseases in the central nervous system. For example, RNA tagging in astrocytes or NG2 cells will allow one to study the transcriptional landscape of these cells throughout the normal development or under certain pathological conditions. Cell ablation experiments could help reveal the critical contributions of specific glial cell types in brain wiring during development and cognitive functions in adulthood. Applied to brain tumor research, cell ablation will help identify important cellular targets for effective therapeutic intervention. Lastly, principles learned from the proposed work will provide a firm foundation for the successful expansion of the system in the future to address a diverse range of exciting topics in neuroscience.
描述(由申请人提供):神经胶质细胞与神经元建立了亲密接触,并有助于在发育过程中策划大脑接线,并促进成年后的神经元功能。因此,重要的是在体内阐明神经胶质功能。但是,仍然缺乏用于研究两种主要神经胶质细胞类型的高度特异性和适应性的小鼠系,成熟的星形胶质细胞和NG2细胞仍缺乏。在这里,我们建议创建鼠标遗传工具,以便以时间控制的方式探究这两种类型的神经胶质细胞的功能。提出的Tet-Off二进制系统由两组小鼠组成:1)在特定类型的神经胶质细胞中表达TTA的驱动线; 2)在TET Operon(TETO)控制下表达细胞消融或转录组分析的转基因的效应线。该系统将允许一个人选择单个驱动器和效应子线来研究神经胶质生物学的特定问题。当与现有的CRE线结合使用时,交叉遗传学可以提供前所未有的细胞类型特异性来分析体内的神经胶质功能。尽管显然很简单,但泄漏,杂色/镶嵌和转基因表达的沉默的问题可能会使这种努力脱轨。经过仔细的准备,我们的实验室现在准备应对这一挑战。通过创建和优化小鼠遗传镶嵌系统获得的基于ES基于ES的敲门策略的丰富经验,我们将使用精心设计的靶向策略来确保转基因表达的忠诚和完整性。同样重要的是,我们已经与神经胶质生物学和小鼠遗传学领域的领导者进行了广泛的咨询,并将这些转基因靶向忠实而特定的转基因表达的最有希望的基因组基因局。我们认为,本赠款中描述的遗传工具将对研究中枢神经系统中正常功能和疾病的作用产生广泛的影响。例如,星形胶质细胞或NG2细胞中的RNA标记将允许在正常发育或某些病理条件下研究这些细胞的转录景观。细胞消融实验可以帮助揭示特定神经胶质细胞类型在成年期间发育和认知功能过程中的关键贡献。应用于脑肿瘤研究,细胞消融将有助于确定重要的细胞靶标,以进行有效的治疗干预。最后,从拟议的工作中学到的原则将为未来成功扩展该系统的牢固基础,以解决神经科学中各种令人兴奋的主题。
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)
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Hui Zong其他文献
Hui Zong的其他文献
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