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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：
10026633
负责人：
Richard Charles Boucher
金额：
$ 74.68万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10026633
关键词：
Agonist Asthma Biological 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 Epithelial Cell Proliferation Epithelial Cells Epithelium Evolution Family Family member Functional disorder Galactosides Gene Expression Genes Glutathione Glutathione Disulfide Goblet Cells Human Human Biology Hyperplasia In Vitro Inflammation Interleukin-13 Link Lung Measures Metabolic Metabolic dysfunction Metabolic stress Metabolism Mitochondria Mucins Mus Oxidative Stress Pathway interactions Phenotype Post-Translational Protein Processing Process 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 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.

本应用探讨了a的翻译后修饰（唾液化）的范式转移假设