Preservation of Limbal Stem Cell Function in Corneal Injury

角膜损伤后角膜缘干细胞功能的保存

• 批准号: 9803337
• 负责人: Heather Chandler
• 金额: $ 41万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803337
• 关键词: Ablation; Acute; Animal Model; Aqueous Humor; Binding; Biochemical; Biological Process; Blindness; Blood Circulation; Blood Vessels; Burn injury; Cardiovascular Diseases; Cell Lineage; Cell Proliferation; Cell membrane; Cell physiology; Chemistry; Chronic; Cicatrix; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cornea; Corneal Diseases; Corneal Injury; Development; Disease; Dose; Engineering; Epithelial; Epithelial Cells; Exhibits; Fibroblasts; Fibrosis; Film; Formulation; Genes; Genetic; Goblet Cells; Health; Health Promotion; Homeostasis; Human; Imaging Device; Infiltration; Injury; Integumentary system; Longevity; Mediating; Membrane; Modeling; Molecular; Mus; Muscle; Mutagenesis; Myofibroblast; Myopathy; Natural regeneration; Ocular Physiology; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Outcomes Research; Pathologic; Pathology; Pharmacology; Physiological; Prevention; Process; Production; Protein Family; Proteins; Protocols documentation; Rattus; Recombinants; Research; Role; Safety; Serum; Signal Transduction; Stem cells; Stress; TRIM Family; Techniques; Testing; Thinness; Tissues; Topical application; Transforming Growth Factor beta; Trauma; Vascularization; Wound Healing; alkalinity; angiogenesis; biochemical tools; cell injury; combat; corneal epithelium; corneal repair; effective therapy; experimental study; extracellular; gene repair; healing; improved; improved outcome; in vivo; injury and repair; limbal; live cell imaging; migration; mouse model; novel; novel therapeutics; preservation; regenerative; repaired; response; scale up; stem; stem cell niche; synergism; tissue regeneration; tissue repair

Project Summary Corneal wound healing is a complex and coordinated process involving injury repair to the epithelial layer and stimulation of limbal stem cell (LSC) proliferation for tissue regeneration. Prevention of excessive stromal myofibroblast activation and vascular ingrowth is also imperative to avoid fibrosis and angiogenesis, which can compromise transparency of the cornea. An approach that can functionally target multiple steps in corneal wound healing may have the potential to significantly improve healing outcomes, leading to novel therapeutic options. This project stems from our novel findings that reveal a vital role for MG53, a tissue repair gene, in modulating LSC function associated with corneal injury-repair. We show that genetic ablation of MG53 leads to injury-induced corneal epithelial thinning, conjunctivalization, stromal fibrosis, and vascularization, all hallmarks of limbal stem cell deficiency (LSCD). Mice with sustained elevation of MG53 in circulation show increased tissue regenerative capacity with enhanced LSC function. MG53 is present in the human tear film, aqueous humor, and corneal epithelial cells, supporting its potential function in corneal homeostasis and wound healing. Using in vivo corneal injury models, we find that MG53 promotes corneal transparency by facilitating epithelial viability and reducing post-injury fibrosis and vascularization. Experiments outlined in this project are centered on testing the hypothesis that MG53 constitutes an active component of the corneal injury- repair and regeneration by maintaining the health of LSCs, as well as controlling the fibrotic response of stromal fibroblasts. We envision that pharmacological formulation to enhance the synergy between MG53 delivery, LSC function, and fibrotic control could be a potentially effective means to treat corneal diseases. The outcome of this research shall have significant translational value in developing potentially effective therapies to treat corneal injury and fibrosis associated with corneal disease.

项目摘要 角膜创伤愈合是一个复杂的协调过程，涉及到上皮层的损伤修复 以及刺激角膜缘干细胞（LSC）增殖以用于组织再生。防止过度 基质肌成纤维细胞活化和血管向内生长对于避免纤维化和血管生成也是必要的， 这会损害角膜的透明度。一种可以在功能上针对多个步骤的方法 在角膜伤口愈合中可能具有显著改善愈合结果的潜力， 治疗选择这个项目源于我们的新发现，揭示了MG 53的重要作用， 基因，调节与角膜损伤修复相关的LSC功能。我们发现MG 53的基因切除 导致损伤诱导的角膜上皮变薄、结膜化、基质纤维化和血管化， 角膜缘干细胞缺乏症（LSCD）的标志。循环中MG 53持续升高的小鼠显示 增加组织再生能力，增强LSC功能。MG 53存在于人泪膜中， 房水和角膜上皮细胞，支持其在角膜稳态中的潜在功能， 伤口愈合使用体内角膜损伤模型，我们发现MG 53通过以下方式促进角膜透明度： 促进上皮细胞存活并减少损伤后纤维化和血管形成。在此概述的实验 该项目的重点是测试MG 53构成角膜损伤的活性成分的假设- 通过维持LSC的健康以及控制LSC的纤维化反应来修复和再生。 基质成纤维细胞我们设想，药理学制剂增强MG 53和MG 54之间的协同作用。 递送、LSC功能和纤维化控制可能是治疗角膜疾病的潜在有效手段。的 这项研究的结果将在开发潜在有效的治疗方法方面具有重要的转化价值 以治疗与角膜疾病相关的角膜损伤和纤维化。