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
• 负责人: Richard Charles Boucher
• 金额: $ 69.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664889
• 关键词: Agonist; Asthma; Biological Markers; CCND1 gene; Carbohydrates; Cell Aging; Cell Communication; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell surface; Cells; Chronic; Data; Disease; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Evolution; Family; Family member; Functional disorder; Gene Expression; Genes; Glutathione; Glutathione Disulfide; Goblet Cells; Human; Human Biology; Hyperplasia; In Vitro; Inflammation; Interleukin-13; Link; Lung; Measures; Membrane; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Mucins; Mus; Oxidative Stress; Pathway interactions; Phenotype; Post-Translational Protein Processing; Process; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Pyroglyphidae; Reporting; Role; Severities; Severity of illness; Sialyltransferases; Sputum; Stimulus; TNF gene; Testing; Time; Tissues; Transgenic Mice; Up-Regulation; airway epithelium; asthma exacerbation; asthmatic; asthmatic airway; asthmatic patient; beta-galactoside; cell type; driving force; epithelial wound; extracellular; glycosylation; improved; in vivo; mTOR inhibition; mouse model; new therapeutic target; novel; oxidation; particle; protein expression; receptor; senescence; sialylation; wound healing

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.

该应用程序探讨了范式转移假设，即翻译后修饰（溶解） 细胞表面（束缚）粘蛋白MUC4驱动末端分化和气道上皮细胞的感应 （AEC）通过抑制表皮生长因子受体（EGFR）家族途径，令人担忧的上皮 伤口修复和哮喘严重程度。我们提出的研究将是第一个专门测试束缚的粘蛋白和 他们的翻译后N-糖基化/溶解度在AEC末端分化和感应中扮演角色。我们的 已发表的数据（Zhou等人）表明，链状粘蛋白MUC4β的溶解度，即MUC4αβSA，对照 杯状细胞末端分化与β-半乳糖苷α2,6-溶解酶-1（ST6GAL1）活性的关系。 ST6GAL1和MUC4β批准降低了AEC增殖能力，并具有额外的已发表数据（inoue et） Al）将AEC增殖与体外异常伤口修复相关联。降低了AEC增殖能力 可能反映了EGFR家族成员ERBB2的激活降低，ERBB2是MUC4β的已知受体。新数据 确认MUC4和ST6GAL1的高程存在于严重恶化的哮喘中和内部 尘螨挑战小鼠。两种生物学上的升高都与低细胞内谷胱甘肽（GSH）相关联 氧化的谷胱甘肽（GSSG）比（氧化应激）和较低的线粒体和感应基因表达。 平行于体外AEC数据显示T2注射/IL-13改变了细胞内代谢和线粒体， 减少GSH/GSSG，并进一步减少伤口修复。然而，MUC4β和/或ITS的总体影响 对上皮细胞表型，细胞感应和这些变化的机制有助于 严重的哮喘尚不清楚。这里提出的研究将彻底评估 粘蛋白，粘蛋白溶解和感应途径（S），同时使用使用的功能重要性 原代人AEC细胞培养和转基因小鼠模型。提出的三个目标将：1）阐明 MUC4β和MUC4βSA对AEC终端分化，敏感和 在体外伤口修复，2）测试MUC4βSA-AEC相互作用对粘蛋白分泌，杯状细胞的功能影响 哮喘小鼠模型中的增生/末端分化，敏感和伤口修复，3）定义 人哮喘患者中MUC4βSA与敏感性和AEC表型的关系。这些并发目标 会迭代地开发将粘蛋白，其糖化和基本感应相关的上皮链接的数据 确定严重哮喘治疗高度新颖的靶标的过程。

项目成果

Impact of a pollution breach at a coke oven factory on asthma control in nearby vulnerable adults.

• DOI: 10.1016/j.jaci.2021.04.011
• 发表时间: 2021-07
• 期刊: The Journal of allergy and clinical immunology
• 作者: Byrwa-Hill BM;Presto AA;Wenzel S;Fabisiak JP
• 通讯作者: Fabisiak JP

Determining asthma endotypes and outcomes: Complementing existing clinical practice with modern machine learning.

• DOI: 10.1016/j.xcrm.2022.100857
• 发表时间: 2022-12-20
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Ray, Anuradha;Das, Jishnu;Wenzel, Sally E.
• 通讯作者: Wenzel, Sally E.

Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes.

• DOI: 10.1164/rccm.202009-3631ci
• 发表时间: 2021-04-01
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Wenzel SE

Real-time imaging of asthmatic epithelial cells identifies migratory deficiencies under type-2 conditions.

• DOI: 10.1016/j.jaci.2021.08.027
• 发表时间: 2022-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Jin M;Watkins S;Larriba Y;Wallace C;St Croix C;Zhou X;Zhao J;Peddada S;Wenzel SE
• 通讯作者: Wenzel SE

Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes.

支气管上皮细胞对吸入皮质类固醇的转录反应决定了严重的哮喘结果。

• DOI: 10.1016/j.jaci.2023.01.028
• 发表时间: 2023
• 期刊: The Journal of allergy and clinical immunology
• 作者: Ginebaugh,ScottP;Hagner,Matthias;Ray,Anuradha;Erzurum,SerpilC;Comhair,SuzyAA;Denlinger,LorenC;Jarjour,NizarN;Castro,Mario;Woodruff,PrescottG;Christenson,StephanieA;Bleecker,EugeneR;Meyers,DeborahA;Hastie,AnnetteT;Moore
• 通讯作者: Moore