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Molecular Mechanisms of corneal wound repair

角膜伤口修复的分子机制

基本信息

批准号：
10674734
负责人：
Vickery E Trinkaus-Randall
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674734
关键词：
Actins Adaptor Signaling Protein Affect Agonist Area Basement membrane Biochemical Biological Biological Assay Blindness Blood-Retinal Barrier Cell Shape Cells Central Nervous System Communication Complex Cornea Corneal Injury Cytoskeletal Modeling Cytoskeleton Data Defect Diabetes Mellitus Diabetic mouse Diffuse Endocytosis Epithelial Cells Epithelium Event Eye Focal Adhesions Goals Health Homeostasis Impaired wound healing Impairment In Vitro Inflammation Injury Ions Ligation Mediating Mediator Medical Care Costs Methodology Microvascular Dysfunction Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Organizational Change Pain Pathogenesis Pathology Persons Play Process Proteins Quality of life Reaction Recurrence Regulation Reporting Research Personnel Risk Role Signal Transduction Stains Surface Technology Therapeutic Tissues Traction Type 2 diabetic Tyrosine Phosphorylation Vision World Health Organization antagonist cell motility corneal epithelial wound healing corneal epithelium diabetic diabetic ulcer diabetic wound healing epithelial injury epithelial repair epithelial wound healing improved live cell imaging mechanotransduction member mouse model non-diabetic painful neuropathy protein degradation protein expression response response to injury sensor wound wound healing

项目摘要

According to the World Health Organization, type 2 diabetes is one of the leading pathologies that increases the risk of improper wound healing and is now considered to be one of the leading causes of preventable blindness. Upon injury, adjacent epithelial cells at the wound edge must communicate and coordinate their response to move forward. Our goal in this proposal is to examine if the interactions between P2X7 and pannexin1 are critical for homeostasis and wound repair. We have evidence that pannexin1 mediates P2X7-induced communication and cell motility. These 2 proteins are critical for ion mobilization, ATP transport and signaling complexes that play roles in inflammation and pain. Other investigators have shown that P2X7 has a role in the pathogenesis of type 2 diabetes including microvascular complications, impaired blood retinal barrier and neuropathic pain (Solini and Novak (2019). We and our collaborators have demonstrated in corneal epithelium that: 1. P2X7 and pannexin1 localization changes with injury and is enhanced near the leading edge of control corneas; 2. Inhibition of P2X7 diminishes communication between cells, alters components of motility and alters tyrosine phosphorylation of focal adhesion and adaptor proteins; 4. P2X7 and pannexin1 interact in vitro and we have preliminary data demonstrating the interaction of P2X7 and pannexin1 in control mice using proximity ligation assays; 5. We have preliminary data that there is minimal difference in pannexin1 in unwounded control and diabetic corneal epithelium; however the response to injury differs; and 6. Inhibition of pannexin1 impedes cell migration in control corneas and in vitro. These led us to hypothesize that P2X7- pannexin1 interaction in corneal epithelium is required for effective cell-cell communication and signaling in response to injury and is needed to regulate the cytoskeleton and forces required for cell motility. The specific aims that we will address are: determine how changes in association of purinoreceptors and pannexin1 are regulated during corneal wound healing; determine if inhibition and/or activation of these 2 proteins changes the organization of the actin cytoskeleton and cell motility and determine if wound healing and motility is mediated by a force exerted through the pannexin-P2X7 interaction and if it is affected by substrate stiffness. Our data suggest the potential for therapeutic approaches to treat delayed corneal epithelial would healing, and recurrent corneal erosions in type 2 diabetes.

根据世界卫生组织的数据，2型糖尿病是人类最主要的疾病之一