The function of LIN28B and follistatin in supporting cell reprogramming and hair cell regeneration in the murine cochlea
LIN28B 和卵泡抑素在支持小鼠耳蜗细胞重编程和毛细胞再生中的功能
基本信息
- 批准号:10366493
- 负责人:
- 金额:$ 53.75万
- 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:2021-12-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ActivinsAddressAdolescentAdultAllelesAttenuatedAuditoryBiological AssayCRISPR/Cas technologyCell ProliferationCellsCochleaCre lox recombination systemCuesDataDiphtheria ToxinDiseaseDoxycyclineEarFluorescent in Situ HybridizationFollistatinGene Expression ProfileGenerationsGenesHair CellsHearingHumanIn VitroKnock-outLabyrinthLoxP-flanked alleleMediatingMitoticMusNatural regenerationNeonatalOrganoidsPersonsPublishingRNA-Binding ProteinsRegenerative capacityRegenerative responseRoleSignal TransductionSupporting CellTestingTherapeuticTransgenesTransgenic MiceTransgenic OrganismsTraumaUp-Regulationantagonistbasecell determinationcell injurycochlear developmentdeafnessexperimental studygene functiongene networkhair cell regenerationhearing impairmenthearing restorationin vitro Modelin vivoin vivo regenerationinsightmature animalmouse geneticsmouse modelneonatal micenotch proteinnoveloverexpressionparalogous genepluripotencyprogenitorranpirnaseregenerativerepair strategyresponsesingle moleculesingle-cell RNA sequencingsoundtooltranscriptome
项目摘要
Project summary
Our proposed study aims to address the function of LIN28B and follistatin in supporting cell reprogramming and
hair cell regeneration in the murine cochlea. Loss of auditory hair cells (HCs) due to disease or trauma is
permanent and is a leading cause for hearing impairments and deafness in humans. Immature auditory
supporting cells (SCs) do regenerate HCs in response to damage but their ability to regenerate lost HCs rapidly
declines as SCs undergo maturation and little to no HC regeneration is observed in adult animals. We recently
uncovered that the RNA binding protein LIN28B and its paralog LIN28A control the regenerative capacity of
cochlear SCs in neonatal cochlear organoids and explants. Whether LIN28A/B has a similar role in cochlear HC
regeneration in vivo has yet to be tested. Furthermore, our recent in vitro studies suggest that LIN28B promotes
HC regeneration through reprogramming SCs into progenitor-like cells and that such state transition can be
further enhanced by the co-activation of the Activin antagonist follistatin. However, whether SCs truly activate a
transitional progenitor-like state during HC regeneration and if so, how LIN28B and FST may influence such
state transition are still unresolved. In our proposed study we will use mouse genetic tools to address whether
LIN28A/B regulates spontaneous cochlear HC regeneration in the immature cochlea in vivo (aim1). Furthermore,
we will use single cell RNA sequencing and single molecule FISH to determine whether LIN28B reprograms
cochlear SCs into progenitor-like cells during HC regeneration (aim2). Moreover, to establish how LIN28B and
FST enhance SC reprogramming and subsequent HC regeneration we will manipulate the function of potential
LIN28B and FST effector genes using lentiviral overexpression and CRISPR-Cas9-mediated knockout strategies
in cochlear organoids (aim3). Finally, we will determine whether co-expression of LIN28B and FST with Atoh1
enables SCs to regenerate cochlear HCs in the mature cochlea in vivo (aim4).
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)
会议论文数量(0)
专利数量(0)
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ANGELIKA DOETZLHOFER其他文献
ANGELIKA DOETZLHOFER的其他文献
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{{ truncateString('ANGELIKA DOETZLHOFER', 18)}}的其他基金
The function of LIN28B and follistatin in supporting cell reprogramming and hair cell regeneration in the murine cochlea
LIN28B 和卵泡抑素在支持小鼠耳蜗细胞重编程和毛细胞再生中的功能
- 批准号:
10513325 - 财政年份:2021
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
听觉支持细胞分化和维持中的Notch信号通路
- 批准号:
8620548 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance
听觉支持细胞分化和维持中的Notch信号通路
- 批准号:
9759912 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
Notch信号通路在听觉支持细胞分化和维持中的作用
- 批准号:
8233258 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
Notch信号通路在听觉支持细胞分化和维持中的作用
- 批准号:
8915297 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
Notch信号通路在听觉支持细胞分化和维持中的作用
- 批准号:
8429496 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance
听觉支持细胞分化和维持中的Notch信号通路
- 批准号:
9239014 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
Notch信号通路在听觉支持细胞分化和维持中的作用
- 批准号:
8812731 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance
听觉支持细胞分化和维持中的Notch信号通路
- 批准号:
9358710 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
Notch signaling pathways in auditory support cell differentiation and maintenance
Notch信号通路在听觉支持细胞分化和维持中的作用
- 批准号:
8084909 - 财政年份:2011
- 资助金额:
$ 53.75万 - 项目类别:
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