miRNAs regulate lung epithelial progenitor cells in development and injury repair
miRNA 调节肺上皮祖细胞的发育和损伤修复
基本信息
- 批准号:8383341
- 负责人:
- 金额:$ 9.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectApicalApoptosisBehaviorCell Differentiation processCell ProliferationCellsCellular biologyCommitDefectDevelopmentDistalEmbryoEpithelialEpithelial CellsEpitheliumEquilibriumExhibitsFeedbackGene ExpressionGenetic TranscriptionHomeostasisInjuryLungLung diseasesMediatingMessenger RNAMicroRNAsModelingMusNaphthaleneNatural regenerationOrganPathway interactionsPhasePhenotypePlayRegulationResearchRoleSignal PathwayStem cellsSystemTherapeuticTransgenic OrganismsTranslational ResearchTranslationsUndifferentiatedWorkairway epitheliumcell behaviorcell typegain of functionhuman DICER1 proteininjuredinjured airwayinjury and repairinsightlung developmentlung injurymutantoverexpressionprecursor cellpreventprogenitorrepairedresponse to injurystem cell populationtranscription factor
项目摘要
DESCRIPTION (provided by applicant): Lung epithelial progenitor cells are essential for development and adult airway regeneration and repair. The mechanisms controlling their behaviors including proliferation and differentiation during development and the progression of airway injury repair are largely unknown. MicroRNAs (miRNAs) are crucial modulators of gene expression, yet their involvement as regulators of lung epithelial progenitor cells is still poorly
understood. Recently, We have demonstrated that miR-302/367 is a direct target of Gata6 -a transcription factor essential for proper lung development and airway regeneration- and regulates the balance of lung epithelial progenitor cell proliferation and differentiation as well s cell apical-basal polarity. We have begun to explore the importance of miR-302/367-mediated lung epithelial progenitor development. Overexpression of miR-302/367 in developing airway epithelium causes expansion of Sox2+ proximal and Sox9+ distal progenitor cells and decreased airway epithelial cell differentiation. Notably, our recent studies reveal that expression of miR- 302/367 is markedly increased in naphthalene-injured lungs compared to control uninjured lungs, suggesting a potential role for miR-302/367 in mediating lung epithelial gene transcription and the injury response during airway repair and regeneration. Therefore, my working hypothesis in this proposal is that miR-302/367 functions as components of a Gata6-dependent regulatory network involving multiple positive and negative feedback loops to modulate proliferation and differentiation of lung epithelial progenitor cells. A better understanding of how miR-302/367 regulates the behaviors of lung epithelial progenitor cells during airway epithelium development and regeneration in response to injury will provide important insights into multiple lung diseases. This will be accomplished by pursuing two specific aims: Specific Aim 1. K99 Phase: Determine the role of miR-302/367 in modulating the behaviors of lung epithelial progenitor cells during airway epithelium development and regeneration after injury. a) Determine the effects of conditional gain- and loss-of-miR-302/367 on lung epithelial progenitor cell development using ROSA-miR- 302/367 and floxed miR-302/367 mouse lines. b) Determine whether decreased expression of Wnt5a is responsible for the expansion of lung epithelial progenitors in miR-302/367 gain of function mutants. c) Determine the requirement of miR-302/367 for homeostasis and regeneration in airway epithelium. Specific Aim 2. R00 Phase: Determine the mechanisms underlying the regulation of epithelial progenitor cell behaviors by miR-302/367 in airway epithelium development and regeneration. a) Characterize miR-302/367 expressing cells in lung epithelium during development and airway regeneration after injury. b) Determine the direct targets and downstream signaling pathways regulated by miR-302/367 in developing lung. c) Determine whether modulation of specific miR-302/367-regulated targets or pathways would enhance airway epithelium repair and regeneration.
描述(由申请人提供):肺上皮祖细胞对于发育以及成人气道再生和修复至关重要。控制其行为的机制,包括发育过程中的增殖和分化以及气道损伤修复的进展,在很大程度上尚不清楚。 MicroRNA (miRNA) 是基因表达的重要调节剂,但它们作为肺上皮祖细胞调节剂的作用仍然很少
明白了。 最近,我们证明 miR-302/367 是 Gata6(一种对肺正常发育和气道再生至关重要的转录因子)的直接靶标,并调节肺上皮祖细胞增殖和分化以及细胞顶端-基底极性的平衡。我们已经开始探索 miR-302/367 介导的肺上皮祖细胞发育的重要性。发育中的气道上皮中 miR-302/367 的过度表达会导致 Sox2+ 近端祖细胞和 Sox9+ 远端祖细胞的扩增,并减少气道上皮细胞的分化。值得注意的是,我们最近的研究表明,与未损伤的对照肺相比,萘损伤的肺中 miR-302/367 的表达显着增加,这表明 miR-302/367 在介导肺上皮基因转录和气道修复和再生过程中的损伤反应中具有潜在作用。因此,我在本提案中的工作假设是,miR-302/367 作为 Gata6 依赖性调节网络的组成部分发挥作用,涉及多个正反馈环和负反馈环,以调节肺上皮祖细胞的增殖和分化。 更好地了解 miR-302/367 在气道上皮发育和损伤再生过程中如何调节肺上皮祖细胞的行为,将为多种肺部疾病提供重要的见解。 这将通过追求两个具体目标来实现: 具体目标 1. K99 阶段:确定 miR-302/367 在气道上皮发育和损伤后再生过程中调节肺上皮祖细胞行为中的作用。 a)使用ROSA-miR-302/367和floxed miR-302/367小鼠系确定miR-302/367的条件获得和丢失对肺上皮祖细胞发育的影响。 b)确定Wnt5a表达的降低是否与miR-302/367功能获得突变体中肺上皮祖细胞的扩增有关。 c) 确定 miR-302/367 对气道上皮稳态和再生的需求。 具体目标 2. R00 阶段:确定 miR-302/367 在气道上皮发育和再生中调节上皮祖细胞行为的机制。 a) 表征肺上皮在发育和损伤后气道再生过程中表达 miR-302/367 的细胞。 b) 确定发育中肺中 miR-302/367 调节的直接靶点和下游信号通路。 c) 确定特定 miR-302/367 调节靶点或途径的调节是否会增强气道上皮修复和再生。
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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Ying Tian其他文献
Ying Tian的其他文献
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{{ truncateString('Ying Tian', 18)}}的其他基金
Regulation of distal lung epithelial regeneration by microRNA-Hippo pathway
microRNA-Hippo通路调控远端肺上皮再生
- 批准号:
9886081 - 财政年份:2016
- 资助金额:
$ 9.28万 - 项目类别:
Regulation of distal lung epithelial regeneration by microRNA-Hippo pathway
microRNA-Hippo通路调控远端肺上皮再生
- 批准号:
9080523 - 财政年份:2016
- 资助金额:
$ 9.28万 - 项目类别:
miRNAs regulate lung epithelial progenitor cells in development and injury repair
miRNA 调节肺上皮祖细胞的发育和损伤修复
- 批准号:
8848109 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
miRNAs regulate lung epithelial progenitor cells in development and injury repair
miRNA 调节肺上皮祖细胞的发育和损伤修复
- 批准号:
8827912 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
miRNAs regulate lung epithelial progenitor cells in development and injury repair
miRNA 调节肺上皮祖细胞的发育和损伤修复
- 批准号:
9063142 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
miRNAs regulate lung epithelial progenitor cells in development and injury repair
miRNA 调节肺上皮祖细胞的发育和损伤修复
- 批准号:
8536357 - 财政年份:2012
- 资助金额:
$ 9.28万 - 项目类别:
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