Mucin sialylation drives epithelial cell senescence and severe asthma

粘蛋白唾液酸化导致上皮细胞衰老和严重哮喘

基本信息

项目摘要

This application explores the paradigm shifting hypothesis that post-translational modification (sialylation) of a cell surface (tethered) mucin, MUC4, drives terminal differentiation and senescence of airway epithelial cells (AECs) through inhibition of epidermal growth factor receptor (EGFR) family pathways, worsening epithelial wound repair and asthma severity. Our proposed studies will be the first to specifically test tethered mucins and their post-translational N-glycosylation/sialylation for a role in AEC terminal differentiation and senescence. Our published data (Zhou et al) demonstrate that sialylation of the tethered mucin, MUC4β, i.e., MUC4α βSA, controls goblet cell terminal differentiation as a function of β-galactoside α2,6-sialyltransferase-1 (ST6GAL1) activity. Both ST6GAL1 and MUC4β critically lower AEC proliferative capacity, with additional published data (Inoue et al) linking diminished AEC proliferation to abnormal wound repair in vitro. Reduced AEC proliferative capacity may reflect reduced activation of the EGFR family member, ErbB2, a known receptor for MUC4β. New data confirm that elevations in MUC4 and ST6GAL1 are present in severe exacerbation-prone asthma and in house dust mite challenged mice. Elevations in both biologically associate with low intracellular glutathione (GSH) to oxidized glutathione (GSSG) ratios (oxidative stress) and lower mitochondrial and senescence gene expression. Parallel in vitro AEC data show T2 inflammation/IL-13 alters intracellular metabolism and mitochondria, decreases GSH/GSSG, and further decreases wound repair. Yet, the overall impact of MUC4β and/or its sialylation to epithelial cell phenotypes, cell senescence, and the mechanisms by which these changes contribute to severe asthma are unclear. The studies proposed here will comprehensively evaluate the intersection of mucins, mucin sialylation, and senescence pathway(s), while robustly testing their functional importance using primary human AEC cell cultures and transgenic mouse models. The three proposed aims will: 1) elucidate the mechanistic and functional impact of MUC4β and MUC4βSA on AEC terminal differentiation, senescence and wound repair in vitro, 2) test the functional impact of Muc4βSA-AEC interactions on mucin secretion, goblet cell hyperplasia/terminal differentiation, senescence, and wound repair in an asthma mouse model and 3) define the relationship of MUC4βSA to senescence and AEC phenotypes in human asthma patients. These concurrent aims will iteratively develop data that link mucins, their sialylation and fundamental senescence-related epithelial processes to identify highly novel targets for treatment of severe asthma.
本应用探讨了a的翻译后修饰(唾液化)的范式转移假设

项目成果

期刊论文数量(0)
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Richard Charles Boucher其他文献

Richard Charles Boucher的其他文献

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{{ truncateString('Richard Charles Boucher', 18)}}的其他基金

UNC Research Training Program in Respiratory Diseases and Critical Care
北卡罗来纳大学呼吸系统疾病和重症监护研究培训计划
  • 批准号:
    10714527
  • 财政年份:
    2023
  • 资助金额:
    $ 74.68万
  • 项目类别:
The molecular and cellular mechanisms of the STAT3 mutation-mediated pulmonary disorder in Autosomal Dominant Hyper IgE Syndrome (AD-HIES)
常染色体显性高 IgE 综合征 (AD-HIES) STAT3 突变介导的肺部疾病的分子和细胞机制
  • 批准号:
    10393987
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
Project 2: Why are mucins so gigantic and is it safe/effective to sever them therapeutically?
项目 2:为什么粘蛋白如此巨大?在治疗上切断它们是否安全/有效?
  • 批准号:
    10684198
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
Core A: Administrative/Biostatistics Core
核心 A:行政/生物统计学核心
  • 批准号:
    10684186
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
The molecular and cellular mechanisms of the STAT3 mutation-mediated pulmonary disorder in Autosomal Dominant Hyper IgE Syndrome (AD-HIES)
常染色体显性高 IgE 综合征 (AD-HIES) STAT3 突变介导的肺部疾病的分子和细胞机制
  • 批准号:
    10584596
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
Diversity Supplement for PhD student Shamarie King under Multi-Scale Investigations of Respiratory Mucus/Mucin Structure and Function in Health and Disease
博士生 Shamarie King 在健康和疾病中呼吸道粘液/粘蛋白结构和功能的多尺度研究中的多样性补充
  • 批准号:
    10852415
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
Multi-Scale Investigations of Respiratory Mucus/Mucin Structure and Function in Health and Disease
健康和疾病中呼吸道粘液/粘蛋白结构和功能的多尺度研究
  • 批准号:
    10684185
  • 财政年份:
    2022
  • 资助金额:
    $ 74.68万
  • 项目类别:
Mucin sialylation drives epithelial cell senescence and severe asthma
粘蛋白唾液酸化导致上皮细胞衰老和严重哮喘
  • 批准号:
    10206266
  • 财政年份:
    2020
  • 资助金额:
    $ 74.68万
  • 项目类别:
Mucin sialylation drives epithelial cell senescence and severe asthma
粘蛋白唾液酸化导致上皮细胞衰老和严重哮喘
  • 批准号:
    10664889
  • 财政年份:
    2020
  • 资助金额:
    $ 74.68万
  • 项目类别:
Mucin sialylation drives epithelial cell senescence and severe asthma
粘蛋白唾液酸化导致上皮细胞衰老和严重哮喘
  • 批准号:
    10434719
  • 财政年份:
    2020
  • 资助金额:
    $ 74.68万
  • 项目类别:

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Testing the effectiveness of the biological drug, Tezepelumab, in patients with coexisting allergic rhinitis and allergic asthma
测试生物药物 Tezepelumab 对同时患有过敏性鼻炎和过敏性哮喘的患者的有效性
  • 批准号:
    490921
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  • 批准号:
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Air Pollution, Stress and Asthma Morbidity Risk: Role of Biological and Geospatial Markers
空气污染、压力和哮喘发病风险:生物和地理空间标记的作用
  • 批准号:
    10216007
  • 财政年份:
    2021
  • 资助金额:
    $ 74.68万
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Air Pollution, Stress and Asthma Morbidity Risk: Role of Biological and Geospatial Markers
空气污染、压力和哮喘发病风险:生物和地理空间标记的作用
  • 批准号:
    10615633
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    2021
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性别作为生物变量:先天防御调节剂 (IDR) 肽在哮喘中的免疫调节机制
  • 批准号:
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    Studentship Programs
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哮喘与肥胖之间关联的潜在生物学机制
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    17K09599
  • 财政年份:
    2017
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Childhood Asthma, Susceptibility and Biological Activity of Ambient Particles
儿童哮喘、环境颗粒物的易感性和生物活性
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儿童哮喘、环境颗粒物的易感性和生物活性
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儿童哮喘、环境颗粒物的易感性和生物活性
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    7685408
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    2008
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    $ 74.68万
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哮喘粘液栓的表型和生物学特征
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    2005
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