Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
基本信息
- 批准号:10407550
- 负责人:
- 金额:$ 55.93万
- 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:2020-06-01 至 2023-03-03
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAcute Lung InjuryAllergensAlveolarAlveolar MacrophagesAnimalsAntibodiesApplications GrantsCCL2 geneCell CountCell Differentiation processCell physiologyCellsChronicChronic Obstructive Pulmonary DiseaseDataEmbryoEpidermal Growth Factor ReceptorEpithelial CellsEvaluationExposure toFOXM1 geneFlow CytometryGenesGeneticGenetic TranscriptionGoblet CellsHistologicHistologyHouse Dust Mite AllergensHumanIn VitroInflammationInflammation MediatorsInflammatoryInterleukin-13Knockout MiceLasersLungMAP Kinase GeneMUC5AC geneMatrix MetalloproteinasesMechanicsMetaplastic CellMethylcholanthreneModelingMolecularMolecular TargetMucinousMucous body substanceMusMyeloid CellsPathogenesisPathway interactionsPatientsPeptide HydrolasesPharmacologyProductionProteinsPulmonary EmphysemaPulmonary InflammationRattusRespiratory physiologyRoleSTAT3 geneSignal PathwaySmokingTestingTransgenesTransgenic OrganismsTreatment EfficacyType II Epithelial Receptor CellUbiquitinationairway epitheliumairway remodelingalveolar epitheliumalveolar type II cellasthma modelcell typechemokinechronic respiratory diseasecigarette smokeefficacy evaluationexperimental studyexposure to cigarette smokeforkhead proteingain of functiongenetic approachhigh throughput screeningimprovedin vivoinfluenza infectioninhibitorloss of functionlung carcinogenesismacrophagemonocytemouse geneticsmulticatalytic endopeptidase complexnoveloverexpressionpreventrecruitresponsesmall moleculetherapeutic evaluationtherapeutic targettherapy outcometranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY. COPD is a severe chronic respiratory disease, which is associated with smoking and
characterized by chronic lung inflammation, emphysema, airway remodeling and goblet cell metaplasia.
Identification of new molecular targets is needed to improve therapeutic outcomes in COPD patients. Our grant
application will explore the role of Forkhead transcription factor FOXM1 as a potential therapeutic target in
mouse and rat COPD models. FOXM1 is an embryonic transcription factor, which is not expressed in
quiescent lungs but aberrantly induced during lung carcinogenesis. We provide preliminary data demonstrating
that FOXM1 is activated in airway epithelial cells, macrophages and type II cells of COPD patients and mice
exposed to cigarette smoke (CS). Increased expression of FOXM1 in mouse and human lungs is associated
with emphysema and goblet cell metaplasia. Transgenic overexpression of FOXM1 in alveolar type II cells
exacerbated lung inflammation, leading to emphysema. Genetic deletion of Foxm1 gene from myeloid cells,
including macrophages and monocytes, decreased pulmonary inflammation after acute lung injury. Genetic
ablation of Foxm1 from airway club cells decreased goblet cell metaplasia caused by house dust mite
allergens. While FOXM1 is increased in human COPD and mouse genetic data suggest that FOXM1 is critical
goblet cell metaplasia, pulmonary inflammation and alveolar remodeling, molecular mechanisms regulated by
FOXM1 in COPD remain unknown. We propose to test the hypothesis that FOXM1 increases goblet cell
metaplasia and emphysema in COPD by transcriptionally activating distinct sets of pro-inflammatory and
mucinous genes in alveolar type II cells, airway club cells and macrophages. We will also test the therapeutic
efficacy of novel FOXM1 inhibitor RCM-1 in mouse and rat COPD models. Chronic CS exposure and a
combination of CS and Influenza infection will be used to induce pulmonary inflammation, emphysema and
goblet cell metaplasia. In Aim 1, we will identify molecular mechanisms regulated by FOXM1 in alveolar type II
cells (Aim 1A) and macrophages (Aim 1B) using purified cells and mice with specific ablation of Foxm1 gene
from these cell types. FOXM1 targets will be validated using de-identified human COPD lungs. In Aim 2A, we
will use mice with specific deletion of Foxm1 from airway club cells, to identify FOXM1 target genes critical for
differentiation of club cells into goblet cells in COPD model. In Aim 2B, we will test therapeutic potential of
novel, non-toxic FOXM1-inhibiting small molecule compound, RCM-1, which has been recently discovered in
my lab using a high throughput screen. Altogether, these studies will identify novel molecular mechanisms
critical for COPD pathogenesis and test therapeutic potential of FOXM1 inhibitors in animal COPD models.
项目总结。慢性阻塞性肺病是一种严重的慢性呼吸系统疾病,与吸烟和吸烟有关
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:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 项目类别:
Transcriptional regulation of goblet cell metaplasia
杯状细胞化生的转录调控
- 批准号:
8744367 - 财政年份:2014
- 资助金额:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 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:
$ 55.93万 - 项目类别:
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