Transcriptional regulation of goblet cell metaplasia
杯状细胞化生的转录调控
基本信息
- 批准号:8744367
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-05 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AllergensApplications GrantsAsthmaBindingBiological AssayBoxingCell Differentiation processChronicChronic Obstructive Airway DiseaseClara cellClinicalCystic FibrosisDataDiseaseDoxycyclineEmbryonic DevelopmentEpithelialEpithelial CellsFamilyGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionGoalsGoblet CellsHumanImmunohistochemistryIn VitroInterleukin-13LaboratoriesLasersLung InflammationMalignant NeoplasmsMediatingMediator of activation proteinMetaplasiaModelingMolecularMorbidity - disease rateMucous body substanceMusPathogenesisPathway interactionsPatientsPeptidesPhenotypePlayProductionPromoter RegionsProteinsPyroglyphidaeRegulationRegulatory ElementReporterReverse Transcriptase Polymerase Chain ReactionRoleSignal PathwaySignal TransductionTestingTherapeuticTimeTranscriptional RegulationTransgenesTransgenic MiceUp-RegulationWestern Blottingairway epitheliumairway hyperresponsivenesschromatin immunoprecipitationefficacy testingforkhead proteingain of functionin vivoinhibitor/antagonistloss of functionlung injurymethacholinemortalitymouse modelnew therapeutic targetnovelpreventpromoterpublic health relevanceresearch studyresponsesmall hairpin RNAsmall molecule
项目摘要
DESCRIPTION (provided by applicant): Goblet cell metaplasia, associated with increased mucus production, is a key pathogenic feature of chronic airway disorders, such as asthma, COPD and cystic fibrosis, all of which contribute to significant morbidity and mortality worldwide.
Pharmacological targeting of goblet cell metaplasia represents a significant clinical challenge. Therefore, identification of new molecular mechanisms in airway epithelial differentiation will provide novel therapeutic targets for treatment of chronic airway disorders. Our grant proposal focuses on novel molecular mechanisms in goblet cell differentiation that are regulated by FoxM1, a transcription factor from the Forkhead box (FOX) family. While FoxM1 plays an important role in embryonic development and pathogenesis of various cancers, the role of FoxM1 in chronic airway diseases is unknown. In our preliminary data, FoxM1 was induced in airway epithelial cells of mice with asthma-like diseases caused by OVA, IL-13 and house dust mite extract (HDM). FoxM1 was also induced in airway epithelial cells of human patients with asthma and COPD. Genetic deletion of the Foxm1 gene (CCSP-Cre) or pharmacological inhibition of the FoxM1 protein (ARF peptide) in HDM-challenged airway epithelium effectively diminished goblet cell metaplasia, reduced lung inflammation and decreased airway hyper-responsiveness to methacholine. While these data suggest that FoxM1 plays a key role in asthma pathogenesis, molecular mechanisms regulated by FoxM1 remain uncharacterized. We propose to test the hypothesis that FoxM1 acts downstream of the IL-13/Stat6 pathway to induce expression of goblet cell-specific genes in airway epithelial cells. In Aim I, we will use transgenic mice with FoxM1 "gain-of-function" and "loss-of-function" in airway Clara cells to identify downstream FoxM1 target genes critical for allergen-mediated differentiation of Clara cells into goblet cells. Furthermore, we provide preliminary data demonstrating that IL-13 induces FoxM1 expression in cultured human airway epithelial cells and airway epithelium of transgenic mice. Knockdown of FoxM1 in vitro inhibited differentiation of airway epithelial cells toward goblet cell phenotype in response to IL-13 stimulation. In Aim II, we will determine if FoxM1 is required for IL-13/Stat6 signaling to induce goblet cell differentiation in vivo. The IL-13/Stat6 signaling pathway will be activated using intratracheal administration of IL-13 and a Doxycycline-inducible IL-13 transgene. FoxM1 inhibition will be achieved by a genetic approach (IL-13/ CCSP- Cre/ Foxm1-/- mice) and a pharmacological approach (ARF peptide and novel small molecule FoxM1 inhibitors). These experiments will determine whether inactivation of FoxM1 will prevent or decrease IL- 13/Stat6 signaling in airway epithelial cells in vivo. Altogether, these studies will identify molecular mechanisms regulated by FoxM1 in airway epithelial cells and determine the therapeutic benefit of FoxM1 inhibitors in mouse asthma models.
描述(由申请人提供):杯状细胞化生,与粘液生成增加相关,是慢性气道疾病(如哮喘,COPD和囊性纤维化)的关键致病特征,所有这些疾病都导致全球显著的发病率和死亡率。
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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Vladimir Kalinichenko其他文献
Vladimir Kalinichenko的其他文献
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{{ truncateString('Vladimir Kalinichenko', 18)}}的其他基金
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
- 批准号:
10891764 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
- 批准号:
10055005 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
- 批准号:
10170416 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
- 批准号:
10407550 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Transcriptional Regulation of Endothelial Cells after Acute Lung Injury
急性肺损伤后内皮细胞的转录调控
- 批准号:
9900064 - 财政年份:2018
- 资助金额:
$ 39万 - 项目类别:
Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury
新生儿肺损伤后内皮细胞的转录调控
- 批准号:
10661242 - 财政年份:2018
- 资助金额:
$ 39万 - 项目类别:
Transcriptional regulation of goblet cell metaplasia
杯状细胞化生的转录调控
- 批准号:
9279216 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
Foxf1 Transcription Factor in Development of Pulmonary Capillaries
Foxf1转录因子在肺毛细血管发育中的作用
- 批准号:
9065597 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Fox Transcription Factors in Development of Pulmonary Capillaries
肺毛细血管发育中的 Fox 转录因子
- 批准号:
7414733 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Foxf1 Transcription Factor in Development of Pulmonary Capillaries
Foxf1转录因子在肺毛细血管发育中的作用
- 批准号:
8242633 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:














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