Delineating the role of let-7 microRNA on lung AT2 cell homeostasis, alveolar regeneration, and interstitial lung disease
描述let-7 microRNA对肺AT2细胞稳态、肺泡再生和间质性肺疾病的作用
基本信息
- 批准号:10634881
- 负责人:
- 金额:$ 52.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AT-Hook MotifsATAC-seqAgingAlveolarAlveolitisAlveolusAnimal ModelApoptosisAppearanceArchitectureAutophagocytosisBioenergeticsBiological AssayBleomycinCell AgingCell CompartmentationCell Differentiation processCell SurvivalCell physiologyCellsCellular Metabolic ProcessCharacteristicsChronic lung diseaseCollagenComplexDNADataDefectDepositionDevelopmentEnhancersEnsureEpitheliumExperimental GeneticsFamilyFelis catusFibrosisFunctional disorderGenerationsGenesGeneticGenus HippocampusGoalsHomeostasisHumanHyperplasiaHypoxemiaImmuneImmunofluorescence ImmunologicImpairmentInflammationInjuryInterstitial Lung DiseasesKnockout MiceKnowledgeLipidsLungLung fibrogenesisMeasurementMetabolicMicroRNAsModelingMolecularMorbidity - disease rateMusNatural regenerationNodalOrganellesPathogenicityPathway interactionsPatientsPhysiologicalPlayPluripotent Stem CellsPolycombProcessProliferatingProteinsProto-Oncogene Proteins c-mycPublic HealthPulmonary EmphysemaPulmonary FibrosisPulmonary SurfactantsQuality ControlRegulationRepressionResearchResolutionRoleSomatic CellStressSystemTestingTimeTissue ModelTomatoesTracerTransitional CellUpstream EnhancerWorkage relatedalveolar lamellar bodycell growthdisease diagnosisdrug discoveryeffective therapyhealinghuman tissueidiopathic pulmonary fibrosisimprovedin vivoinsightlipid metabolismlung injurymortalitymouse modelnovel therapeuticspreventprogenitorprogramsrepairedresponsesenescencestemstem cell divisionstem cell fatestem cell populationstem cellssurfactantsurfactant productiontissue repairtranscription factortranscriptomicstransdifferentiation
项目摘要
Project Summary
Interstitial lung diseases (ILDs) including Idiopathic Pulmonary Fibrosis (IPF) are associated with significant
morbidity and mortality. Treatment options for patients with ILD are limited by a lack of understanding of the
pathophysiologic mechanisms. Alveolar type 2 (AT2) cells, the main epithelial progenitor stem cell population in
the lung, are critically important in ILD pathophysiology as they regulate surfactant production and operate as
stem cell progenitors for repair of alveoli after injury via generation of alveolar type 1 (AT1) cells. Disruptions to
the DNA, protein, organellar quality control, and cell metabolism have all been hypothesized to underlie AT2-cell
driven ILD. Recent insights on the AT2 cell states and differentiation trajectories led to the discovery of primed
and cycling AT2 (pAT2 and cAT2) cell subpopulation(s) and alveolar differentiation intermediate (ADI) cells,
which convert into AT1 cells during lung injury. However, the global regulatory mechanisms that contribute to
dysregulated AT2 cell homeostasis and the relationship to impaired AT2 progenitor stem cell renewal are not
well understood. In preliminary work, we found that conditional inactivation of let-7 microRNA clusters specifically
in alveolar AT2 cells in mice promotes spontaneous age-dependent parenchymal remodeling with features of
ILD including pronounced septal alveolar thickening, fibroblastic foci with collagen deposition and pronounced
alveolitis. We also found that let-7 promotes hyperplasia of AT2 cells and the appearance of ADI transitional
cells with a cellular senescence profile. Based on transcriptomic data hypothesize that the let-7 family of
microRNAs serves as an essential coordinator of AT2 cell autophagy & lipid homeostasis, progenitor stem cell
renewal, and AT1 differentiation. In this proposal, we will extend these exciting findings to (1) determine how the
let-7 pathway regulates AT2 progenitor stem cell trajectories and cell differentiation dynamics during ILD; (2)
determine how let-7 pathway impairs AT2 cell surfactant homeostasis and contributes to alterations in autophagy
and lipid metabolism during ILD remodeling; and (3) identify mechanism(s) through which let-7 controls AT2 cell
renewal in mice and humans. The project will elucidate a fundamental repair and regeneration process in the
lung and pave the way for new targetable pathways for drug discovery in the context of IPF.
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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Antony Rodriguez其他文献
Antony Rodriguez的其他文献
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{{ truncateString('Antony Rodriguez', 18)}}的其他基金
Analysis of novel non coding mRNA-like RNAs in mice.
小鼠中新型非编码 mRNA 样 RNA 的分析。
- 批准号:
6859901 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
Analysis of novel non coding mRNA-like RNAs in mice
小鼠中新型非编码 mRNA 样 RNA 的分析
- 批准号:
7105183 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
Analysis of novel non coding mRNA-like RNAs in mice
小鼠中新型非编码 mRNA 样 RNA 的分析
- 批准号:
7275581 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
Analysis of novel non coding mRNA-like RNAs in mice
小鼠中新型非编码 mRNA 样 RNA 的分析
- 批准号:
6908155 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
Analysis of novel non coding mRNA-like RNAs in mice
小鼠中新型非编码 mRNA 样 RNA 的分析
- 批准号:
6793016 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
Analysis of novel non coding mRNA-like RNAs in mice
小鼠中新型非编码 mRNA 样 RNA 的分析
- 批准号:
7272762 - 财政年份:2004
- 资助金额:
$ 52.55万 - 项目类别:
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