Maladaptive epigenetic control of MUC5B transcription in pulmonary fibrosis

肺纤维化中 MUC5B 转录的适应不良表观遗传控制

基本信息

  • 批准号:
    10627598
  • 负责人:
  • 金额:
    $ 50.99万
  • 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:
    2023-07-01 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary In this project, we will define epigenetic and transcriptional mechanisms that result in increased MUC5B expression, distal airway epithelial abnormalities, and associated fibroproliferative phenotypes. Idiopathic pulmonary fibrosis (IPF) has a 5-year mortality rate surpassing many cancers. The G-to-T transversion, rs35705950, is the most potent known risk factor for developing IPF and is located ~ 3 kb upstream of the MUC5B gene. This -3 kb region regulates MUC5B expression, which is increased in IPF, especially in terminal bronchiole-like regions. Bronchioles are a primary site of IPF pathogenesis and feature aberrant epithelial differentiation in disease, promoting local recruitment and activation of fibroblasts. Although rs35705950 and MUC5B are key players in IPF pathogenesis, rs35705950 alone is not sufficient to cause IPF, and we don’t fully understand how MUC5B and rs35705950 promote IPF pathogenesis. Our proposal is based on a two- hit hypothesis that addresses these gaps. We hypothesize that MUC5B overexpression, potentiated by epigenetic changes, primes the bronchiolar epithelium such that a second injurious hit results in aberrant epigenetic regulation, detrimental ER stress and fibroblast activation. Three Aims address this hypothesis. In Aim 1, we will determine molecular control of MUC5B transcription in proximal and distal airway epithelia from unaffected and IPF subjects. This work extends our preliminary data on -3 kb MUC5B enhancer function, and we will specifically test whether the pioneer transcription factor, FOXA2, induces chromatin remodeling, enhancer RNA transcription and MUC5B expression through methods such as ChIP and factor knockdown. In Aim 2 we will identify epigenetic and transcription factor mechanisms that drive abnormal distal airway epithelial cell differentiation in relationship to MUC5B expression and genotypes in IPF. Aim 2 is motivated by our data implicating important roles in IPF for two transcription factors involved in normal airway epithelial differentiation, EHF and GRHL2. Our methods in Aim 2 will include ATAC-seq, nascent transcript sequencing, knockdown and ChIP to define mechanistic roles for these factors in IPF, with extension of our findings into human samples and cells from Muc5b overexpressing mice. In Aim 3, we will investigate the role of airway epithelial epigenetics and MUC5B expression on transcriptional control of ER stress and fibroblast activation in IPF. Aim 3 builds on our data supporting an epigenetic mechanism in detrimental ER stress responses where IPF- derived cells direct the master ER stress regulator, XBP1(S) to interact with open chromatin at motifs for the ATF family of transcription factors. We will extend on these findings through applying ATAC-seq and ChIP-seq to study XBP1(S) genomic occupancy and ATF4 crosstalk in IPF-derived human airway epithelial cells. We will also study fibroblast epigenetics in relationship to airway epithelial abnormalities in IPF. Taken together, these studies will advance our molecular understanding of transcriptional control in IPF pathogenesis and identify new targets for restoring distal airway epithelial function in this devastating disease.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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ANTHONY N GERBER其他文献

ANTHONY N GERBER的其他文献

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{{ truncateString('ANTHONY N GERBER', 18)}}的其他基金

Aspen Lung Conference: Asthma: Pathogenesis, Phenotypes, Therapies and Gaps
阿斯彭肺部会议:哮喘:发病机制、表型、治疗方法和差距
  • 批准号:
    10680832
  • 财政年份:
    2023
  • 资助金额:
    $ 50.99万
  • 项目类别:
Mechanisms and Consequences of Gene Induction by Glucocorticoids in Airway Smooth Muscle
糖皮质激素在气道平滑肌中基因诱导的机制和后果
  • 批准号:
    10446915
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用及对糖皮质激素的反应
  • 批准号:
    8645718
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用以及对糖皮质激素的反应
  • 批准号:
    8459449
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Mechanisms and Consequences of Gene Induction by Glucocorticoids in Airway Smooth Muscle
糖皮质激素在气道平滑肌中基因诱导的机制和后果
  • 批准号:
    10641892
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用及对糖皮质激素的反应
  • 批准号:
    8826799
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用以及对糖皮质激素的反应
  • 批准号:
    8298027
  • 财政年份:
    2012
  • 资助金额:
    $ 50.99万
  • 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
  • 批准号:
    7459012
  • 财政年份:
    2005
  • 资助金额:
    $ 50.99万
  • 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
  • 批准号:
    6956616
  • 财政年份:
    2005
  • 资助金额:
    $ 50.99万
  • 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
  • 批准号:
    7254125
  • 财政年份:
    2005
  • 资助金额:
    $ 50.99万
  • 项目类别:

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