Identification of gene regulatory networks that control proliferative and neurogenic competence in mammalian Müller glia
鉴定控制哺乳动物穆勒神经胶质细胞增殖和神经发生能力的基因调控网络
基本信息
- 批准号:10636825
- 负责人:
- 金额:$ 51.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultCRISPR/Cas technologyCatalogsCell CycleCellsChickChromatinClustered Regularly Interspaced Short Palindromic RepeatsCompetenceDedicationsDegenerative DisorderDiseaseFamilyGene ExpressionGene Expression ProfileGenerationsGenesGliosisGoalsGrowth FactorHourIndividualInjuryMammalsMediatingMolecularMorphologyMuller&aposs cellMusNFIA geneNatural regenerationNeurogliaPhotoreceptorsPredictive FactorProcessProliferatingRadialRepressionRestRetinaRetinal DiseasesRetinal DystrophyRetinal PhotoreceptorsTreatment FactorWorkZebrafishcell typecold blooded vertebratecombinatorialdesignefficacy validationgene functiongene regulatory networkhatchinginsightloss of functionmorphogensmutantneurogenesisnovel strategiesoverexpressionregenerative therapyregenerative treatmentresponse to injuryretinal damageretinal neuronretinal progenitor cellretinal rodstherapy developmenttranscription factor
项目摘要
Project Summary
Müller glia of cold-blooded vertebrates can re-enter the cell cycle and rise to photoreceptors following retinal
injury, while mammals have lost this ability. As part of the NEI Audacious Goals Initiative, we have conducted a
ü
comprehensive analysis of injury-induced changes in gene expression and chromatin accessibility in zebrafish,
chick and mouse M ller glia, allowing us to identify both evolutionarily consüerved and species-specific gene
regulatory networks that regulate glial reprogramming. This has identified a set of dedicated gene regulatory
networks in mice tühat restrict proliferative and neurogenic competence in M ller glia. We aim to use these
findings to gain a more complete insight into the molecular mechanisms that regulate neurogenic competence
in mammalian M ller glia, and to develop treatments that can maximize generation of glial-derived
photoreceptors while simultaneously not depleting the number of existing glia. To do this, we propose to
generate individual loss of function mutants of the top candidate negative regulators of proliferative and
ü
neurogenic competence using AAV-mediated CRISPR/Cas9 gene disruption. We will first validate efficacy of
sgRNAs targeting individual TFs, comprehensively profile chanüges in geüne expression in reactive M ller glia
following loss of function of these genes, and characterize the fate of M ller glia-derived cells. We will then
conduct combinatorial loss of function of negative regulators of M ller glia reprogramming to enhance generation
ü
of glial-derived retinal progenitor cells in wildtype and Nfia/b/x-deficient mice. Finally, we will combine CRISPR-
mediated loss of function analysis with overexpression of Ascl1, Crx and Nrl to enhance generation of M ller
glia-derived rod photoreceptors in both wildtype and dystrophic retina. We predict that these studies may
substantially advance cell-based regenerative treatments aimed at restoring retinal photoreceptors lost due to
blinding diseases.
项目摘要
冷血脊椎动物的Müller神经胶质细胞可以重新进入细胞周期,并在视网膜色素变性后上升为光感受器。
而哺乳动物则失去了这种能力。作为NEI大胆目标计划的一部分,我们进行了一次
ü
全面分析损伤诱导的斑马鱼基因表达和染色质可及性变化,
鸡和小鼠M ller神经胶质细胞,使我们能够识别进化保守和物种特异性基因
调节神经胶质细胞重编程的调节网络。这已经确定了一套专门的基因调控
在小鼠中的网络限制M ller胶质细胞的增殖和神经原性能力。我们的目标是利用这些
这些发现可以更全面地了解调节神经原性能力的分子机制
在哺乳动物M ller神经胶质细胞,并开发治疗,可以最大限度地产生神经胶质源性
光感受器,同时不消耗现有的神经胶质细胞的数量。为此,我们建议
产生增殖和增殖的最佳候选负调节因子的个体功能丧失突变体,
ü
使用AAV介导的CRISPR/Cas9基因破坏的神经原性能力。我们将首先验证
靶向单个TF的sgRNA,全面描述反应性Mller神经胶质细胞中geüne表达的变化
这些基因的功能丧失后,并表征Mller神经胶质衍生细胞的命运。然后我们将
进行Mller胶质细胞重编程负调控因子功能的组合丧失以增强生成
ü
野生型和Nfia/B/x缺陷小鼠中神经胶质源性视网膜祖细胞的生长情况。最后,我们将联合收割机CRISPR-
通过Ascl 1、Crx和Nrl的过表达以增强M ller的产生的介导的功能丧失分析
野生型和营养不良性视网膜中的神经胶质源性视杆细胞。我们预测,这些研究可能
基本上先进的基于细胞的再生治疗,旨在恢复由于
致盲疾病
项目成果
期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ectopic insert-dependent neuronal expression of GFAP promoter-driven AAV constructs in adult mouse retina.
- DOI:10.3389/fcell.2022.914386
- 发表时间:2022
- 期刊:
- 影响因子:5.5
- 作者:
- 通讯作者:
A potential role for somatostatin signaling in regulating retinal neurogenesis.
- DOI:10.1038/s41598-021-90554-3
- 发表时间:2021-05-26
- 期刊:
- 影响因子:4.6
- 作者:Weir K;Kim DW;Blackshaw S
- 通讯作者:Blackshaw S
IReNA: Integrated regulatory network analysis of single-cell transcriptomes and chromatin accessibility profiles.
- DOI:10.1016/j.isci.2022.105359
- 发表时间:2022-11-18
- 期刊:
- 影响因子:5.8
- 作者:Jiang, Junyao;Lyu, Pin;Li, Jinlian;Huang, Sunan;Tao, Jiawang;Blackshaw, Seth;Qian, Jiang;Wang, Jie
- 通讯作者:Wang, Jie
Updates and challenges of axon regeneration in the mammalian central nervous system.
- DOI:10.1093/jmcb/mjaa026
- 发表时间:2020-10-01
- 期刊:
- 影响因子:5.5
- 作者:Qian C;Zhou FQ
- 通讯作者:Zhou FQ
Control of neurogenic competence in mammalian hypothalamic tanycytes.
- DOI:10.1126/sciadv.abg3777
- 发表时间:2021-05
- 期刊:
- 影响因子:13.6
- 作者:Yoo S;Kim J;Lyu P;Hoang TV;Ma A;Trinh V;Dai W;Jiang L;Leavey P;Duncan L;Won JK;Park SH;Qian J;Brown SP;Blackshaw S
- 通讯作者:Blackshaw S
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Seth Blackshaw其他文献
Seth Blackshaw的其他文献
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{{ truncateString('Seth Blackshaw', 18)}}的其他基金
Elucidating and bypassing molecular mechanisms that suppress Muller glia-dependent regeneration of cones in two zebrafish models of chronic retinal damage
阐明和绕过抑制两种慢性视网膜损伤斑马鱼模型中穆勒胶质细胞依赖性视锥细胞再生的分子机制
- 批准号:
10567836 - 财政年份:2023
- 资助金额:
$ 51.19万 - 项目类别:
Development and function of hypothalamic Lhx6-positive neurons
下丘脑 Lhx6 阳性神经元的发育和功能
- 批准号:
10219527 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Identifying gene regulatory networks controlling photoreceptor specification by transcriptomic and epigenomic analysis of retinal development in cone-dominant retina
通过锥体优势视网膜视网膜发育的转录组和表观基因组分析来识别控制光感受器规格的基因调控网络
- 批准号:
10116765 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Identifying gene regulatory networks controlling photoreceptor specification by transcriptomic and epigenomic analysis of retinal development in cone-dominant retina
通过锥体优势视网膜视网膜发育的转录组和表观基因组分析来识别控制光感受器规格的基因调控网络
- 批准号:
10320067 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Development and function of hypothalamic Lhx6-positive neurons
下丘脑 Lhx6 阳性神经元的发育和功能
- 批准号:
10558580 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Development and function of hypothalamic Lhx6-positive neurons
下丘脑 Lhx6 阳性神经元的发育和功能
- 批准号:
10372173 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Identification of gene regulatory networks that control proliferative and neurogenic competence in mammalian Müller glia
鉴定控制哺乳动物穆勒神经胶质细胞增殖和神经发生能力的基因调控网络
- 批准号:
10220984 - 财政年份:2020
- 资助金额:
$ 51.19万 - 项目类别:
Identification of gene regulatory networks that control proliferative and neurogenic competence in mammalian Müller glia
鉴定控制哺乳动物穆勒神经胶质细胞增殖和神经发生能力的基因调控网络
- 批准号:
10411984 - 财政年份:2020
- 资助金额:
$ 51.19万 - 项目类别:
Identification of gene regulatory networks that control proliferative and neurogenic competence in mammalian Müller glia
鉴定控制哺乳动物穆勒神经胶质细胞增殖和神经发生能力的基因调控网络
- 批准号:
10029171 - 财政年份:2020
- 资助金额:
$ 51.19万 - 项目类别:
Generation of viral vectors that use alternative splicing to drive cell type-specific gene expression in the nervous system
生成使用选择性剪接驱动神经系统中细胞类型特异性基因表达的病毒载体
- 批准号:
10012468 - 财政年份:2020
- 资助金额:
$ 51.19万 - 项目类别:
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