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N-glycosylation and ocular surface homeostasis

N-糖基化和眼表稳态

基本信息

批准号：
9533581
负责人：
Pablo Argueso
金额：
$ 49.25万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9533581
关键词：
Address Affect Affinity Aging Anabolism Animal Model Apical Automobile Driving Binding Biological Process Cell Differentiation process Cell Proliferation Cell physiology Cell surface Cells Cellular Stress Clinical Treatment Cornea Critical Pathways Data Disease Epithelial Epithelial Cells Epithelium Extracellular Domain Eye Galectin 3 Genes Glycocalyx Health Health Promotion Hexosamines Homeostasis Human Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Integrin alpha3beta1 Kinetics Laboratories Lectin Longevity Matrix Metalloproteinases Medial Golgi Mediating Metabolic Molecular Mucins Organism Pathologic Pathologic Processes Pathway interactions Pharmacological Treatment Pharmacology Physiological Physiological Processes Polysaccharides Prevention Process Proteins Quality Control RNA interference screen Reaction Regulation Research Role Series Signal Transduction Structure Supplementation TNF gene Therapeutic Therapeutic Uses Translating age related base biological adaptation to stress conjunctiva corneal epithelium crosslink defined contribution endoplasmic reticulum stress experimental study eye dryness genome-wide glycosylation glycosyltransferase improved in vivo mouse model novel novel therapeutics ocular surface prevent receptor receptor binding response senescence

项目摘要

Project Summary/Abstract Disruption of barrier function at the ocular surface epithelia is associated with a wide range of disorders that includes dry eye—an age-related disease affecting millions of people worldwide and whose pharmacological treatment remains unresolved. Terminally differentiated stratified epithelial cells in cornea and conjunctiva maintain barrier function through a specialized protective structure composed of transmembrane mucins, a group of heavily glycosylated proteins characterized by extremely large extracellular domains. Galactosyl residues on mucin glycans are cross-linked on the apical glycocalyx by the multimeric protein galectin-3 to prevent cellular damage. Critical to preventing the decline in cellular function and homeostasis is the hexosamine pathway—a series of anabolic reactions that generate increased synthesis of N-glycan precursors. Activation of the hexosamine pathway leads to increased branching of N-glycans in the medial Golgi and the formation of cell-surface galectin-3 lattices that can modulate cell differentiation. Importantly, metabolic supplementation with hexosamine pathway metabolites is also known to enhance protein quality control mechanisms. Despite these critical roles, the relevance of N-glycosylation and the function of hesoxamine metabolites in ocular surface health and disease remains understudied. We hypothesize that N- glycans have a dynamic role in ocular surface epithelial cells, changing in response to inflammation and driving mucin barrier and stress responses. The long-term objective of this proposal is to determine the contribution of the N-glycan branching in promoting ocular surface health, and whether activation of the hexosamine pathway can be used for therapeutic gain in the eye. The following specific aims will address this objective: (1) to characterize mucin N-glycans in human corneal epithelial cells and their relationship to galectin-3 under normal and pro-inflammatory conditions, (2) to determine the regulatory role of N-glycans in promoting barrier function and reducing stress responses at the ocular surface, and (3) to evaluate whether activation of the hexosamine pathway promotes ocular surface homeostasis. This research will address the largely unstudied function of N-glycans in ocular surface barrier function and stress responses, and explore the potential of pharmacologically activating the hexosamine pathway for the treatment of ocular surface diseases.

项目总结/文摘