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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

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
项目类别：
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

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.

该应用程序探讨了范式转换假设，即翻译后修饰（唾液酸化）细胞表面（束缚）粘蛋白 MUC4 驱动气道上皮细胞的终末分化和衰老（AEC）通过抑制表皮生长因子受体（EGFR）家族途径，使上皮细胞恶化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粘蛋白和它们的翻译后 N-糖基化/唾液酸化在 AEC 终末分化和衰老中发挥作用。我们的已发表的数据（Zhou 等人）表明，拴系粘蛋白 MUC4β（即 MUC4α βSA）的唾液酸化可以控制杯状细胞终末分化作为 β-半乳糖苷 α2,6-唾液酸转移酶-1 (ST6GAL1) 活性的函数。 ST6GAL1 和 MUC4β 均严重降低 AEC 增殖能力，并有其他已发表的数据（Inoue 等人） al) 将 AEC 增殖减少与体外伤口修复异常联系起来。 AEC增殖能力降低可能反映了 EGFR 家族成员 ErbB2（一种已知的 MUC4β 受体）的激活减少。新数据确认 MUC4 和 ST6GAL1 的升高存在于严重易发作哮喘和室内尘螨挑战小鼠。两者的升高在生物学上都与低细胞内谷胱甘肽 (GSH) 相关氧化型谷胱甘肽 (GSSG) 比率（氧化应激）以及较低的线粒体和衰老基因表达。平行体外 AEC 数据显示 T2 炎症/IL-13 改变细胞内代谢和线粒体，降低 GSH/GSSG，并进一步降低伤口修复。然而，MUC4β 和/或其唾液酸化对上皮细胞表型、细胞衰老以及这些变化的机制至严重哮喘尚不清楚。这里提出的研究将综合评估粘蛋白、粘蛋白唾液酸化和衰老途径，同时使用以下方法强有力地测试它们的功能重要性原代人 AEC 细胞培养物和转基因小鼠模型。拟议的三个目标将：1）阐明 MUC4β和MUC4βSA对AEC终末分化、衰老和功能的影响体外伤口修复，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/终末分化、衰老和伤口修复，3) 定义 MUC4βSA 与人类哮喘患者衰老和 AEC 表型的关系。这些共同目标将迭代开发将粘蛋白、其唾液酸化和基本衰老相关上皮细胞联系起来的数据确定治疗严重哮喘的高度新颖的靶标的过程。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
通讯作者：
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
影响因子：
0
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
影响因子：
0
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