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.
项目摘要 在这个项目中,我们将定义导致MUC5B增加的表观遗传和转录机制 表达、远端呼吸道上皮异常和相关的纤维增殖性表型。特发性 肺纤维化(IPF)的5年死亡率超过了许多癌症。G到T的转换, Rs35705950是发生IPF的最大已知风险因子,位于 MUC5B基因。这个-3kb区域调控MUC5B的表达,在IPF中,MUC5B表达增加,特别是在末端 细支气管区。细支气管是IPF发病的主要部位和异常上皮细胞的特征 在疾病中分化,促进成纤维细胞的局部招募和激活。虽然rs35705950和 MUC5B是IPF发病机制中的关键分子,仅靠rs35705950不足以引起IPF,我们也不能 充分了解MUC5B和rs35705950是如何促进IPF发病的。我们的建议是基于两次成功的 解决这些差距的假设。我们假设,表观遗传增强了MUC5B的过度表达 改变,启动细支气管上皮,使第二次损伤性打击导致异常表观遗传 调节,有害的内质网应激和成纤维细胞的激活。有三个目标解决了这一假设。在目标1中,我们 将确定未受影响的近端和远端呼吸道上皮中MUC5B转录的分子控制 和IPF受试者。这项工作扩展了我们关于-3kb MUC5B增强子功能的初步数据,我们将 具体测试先驱转录因子FOXA2是否诱导染色质重塑、增强子 通过芯片、因子敲除等方法进行RNA转录和MUC5B的表达。在《目标2》中,我们 将确定驱动异常远端呼吸道上皮细胞的表观遗传和转录因子机制 IPF分化程度与MUC5B表达及基因分型的关系Aim 2的动机是我们的数据 参与正常呼吸道上皮分化的两个转录因子在IPF中的重要作用 流行性出血热和GRHL2。我们在AIM 2中的方法将包括ATAC-SEQ、新生转录测序、基因敲除 和芯片来定义这些因素在IPF中的机械作用,并将我们的发现扩展到人类 MUC5B过表达小鼠的样本和细胞。在目标3中,我们将研究呼吸道上皮细胞的作用 表观遗传学和MUC5B在内质网应激和成纤维细胞激活转录调控中的作用。目标 3基于我们的数据,支持有害内质网应激反应的表观遗传机制,其中IPF- 衍生细胞指导主要的内质网应激调节因子XBP1(S)与开放染色质相互作用 ATF转录因子家族。我们将通过应用ATAC-SEQ和CHIP-SEQ来扩展这些发现 目的:研究XBP1(S)基因在IPF来源的人呼吸道上皮细胞中的基因组占有率和ATF4串扰。我们会 也要研究成纤维细胞表观遗传学与IPF中呼吸道上皮异常的关系。这些加在一起, 研究将促进我们对IPF发病机制中转录调控的分子理解,并确定 在这种毁灭性的疾病中恢复远端呼吸道上皮功能的新目标。

项目成果

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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:
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:
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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