Transcriptional regulation of goblet cell metaplasia

杯状细胞化生的转录调控

基本信息

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(申请人提供):杯状细胞化生与粘液产生增加相关,是慢性呼吸道疾病的主要致病特征,如哮喘、慢性阻塞性肺疾病和囊性纤维化,所有这些疾病都在全球范围内导致显著的发病率和死亡率。 药理学靶向治疗杯状细胞化生是一项重大的临床挑战。因此,识别呼吸道上皮细胞分化的新分子机制将为慢性呼吸道疾病的治疗提供新的靶点。我们的资助计划集中在杯状细胞分化中受FOXM1调控的新的分子机制,FOXM1是叉头盒(Fox)家族的一种转录因子。虽然FOXM1在胚胎发育和各种癌症的发病机制中发挥着重要作用,但FOXM1在慢性呼吸道疾病中的作用尚不清楚。在我们的初步数据中,FOXM1在由OVA、IL-13和屋尘螨提取物(HDM)引起的哮喘样疾病小鼠的呼吸道上皮细胞中被诱导。FOXM1在哮喘和COPD患者的呼吸道上皮细胞中也被诱导。HDM激发的气道上皮中FOXM1基因的基因缺失(CCSP-CRE)或FOXM1蛋白(ARF肽)的药物抑制有效地减少杯状细胞化生,减少肺部炎症,并降低对乙酰甲胆碱的高反应性。虽然这些数据表明FOXM1在哮喘发病机制中发挥了关键作用,但FOXM1调节的分子机制仍不清楚。我们建议验证FOXM1作用于IL-13/Stat6通路下游以诱导呼吸道上皮细胞杯状细胞特异性基因表达的假设。在目标I中,我们将使用在呼吸道Clara细胞中带有FOXM1“功能获得”和“功能丧失”的转基因小鼠来识别FOXM1下游的靶基因,这些基因对于过敏原介导的Clara细胞向杯状细胞的分化至关重要。此外,我们还提供了初步的数据显示,IL-13可诱导培养的人呼吸道上皮细胞和转基因小鼠的呼吸道上皮细胞表达FOXM1。体外下调FOXM1基因可抑制IL-13刺激下呼吸道上皮细胞向杯状细胞表型的分化。在AIM II中,我们将确定FOXM1是否是IL-13/Stat6信号通路在体内诱导杯状细胞分化所必需的。IL-13/Stat6信号通路将通过气管内注射IL-13和多西环素诱导的IL-13转基因来激活。FOXM1的抑制将通过遗传方法(IL-13/CCSP-CRE/FOXM1-/-小鼠)和药理学方法(ARF肽和新型小分子FOXM1抑制剂)实现。这些实验将确定FOXM1的失活是否会阻止或减少体内呼吸道上皮细胞中的IL-13/Stat6信号转导。总之,这些研究将确定FOXM1在呼吸道上皮细胞中调节的分子机制,并确定FOXM1抑制剂在小鼠哮喘模型中的治疗益处。

项目成果

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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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