Inhibiting neovascularization for corneal wound healing

抑制新生血管形成促进角膜伤口愈合

基本信息

批准号：
10366187
负责人：
Heather Chandler
金额：
$ 41万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10366187
关键词：
Ablation Acute Animals Antibodies Aqueous Humor Attenuated Binding Biochemical Blindness Blood Vessels Bone Marrow Bone Marrow Transplantation Burn injury CASP1 gene CRISPR/Cas technology Cell Death Cell membrane Cell model Cells Clinical Cornea Corneal Diseases Corneal Injury Corneal Neovascularization Cytoplasmic Granules Data Development Disease Disulfiram Doxycycline Epithelial Epithelial Cells Etiology Fibrosis Film Genetic Growth Health Homeostasis Human Immune In Vitro Infiltration Inflammation Inflammatory Injury Innate Immune Response Interleukin-1 beta Knock-out Liposomes Mediating Membrane Modeling Molecular Mus Mutagenesis Neutrophil Infiltration Neutrophilic Infiltrate Operative Surgical Procedures Optics Outcome Outcomes Research Pathologic Pathway interactions Pattern Peptide Hydrolases Peroxidases Persons Pharmacology Phase Play Prevention Process Protein Family Proteins Publishing Reactive Oxygen Species Recombinants Regulation Resistance Rodent Model Role Safety Signal Transduction Structure TRIM Family Testing Tissues Topical application Transforming Growth Factor beta Trauma Tumor-infiltrating immune cells Vascularization Vision Visual impairment Wild Type Mouse alkalinity corneal epithelial wound healing corneal epithelium corneal regeneration corneal scar cytokine effective therapy experimental study gene repair healing immune function improved in vivo in vivo Model inhibitor injured injury and repair live cell imaging macrophage mutant neovascularization neutrophil novel novel therapeutics overexpression oxidative damage prevent protective effect repair function repaired reparative process response tissue repair tool wound healing

项目摘要

Project Summary The healthy cornea is an avascular tissue which is a requirement for optical clarity and good vision. Diseases in which the optical clarity of the cornea is lost are the third most common cause of blindness worldwide. Various disease conditions, such as corneal injury, can result in inflammation and the pathological ingrowth of vessels into the cornea, a process known as corneal neovascularization (CNV). Prevention of vascular ingrowth is imperative in maintaining the health and transparency of the cornea. We have previously demonstrated that MG53, a tissue repair gene, can promote corneal wound healing in both the epithelium and stroma. We recently discovered that MG53 can modulate corneal inflammation and vascularization. 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. MG53 is present in the human tear film, aqueous humor, and corneal epithelial cells, supporting its potential function in corneal homeostasis and wound healing. We show that genetic ablation of MG53 leads to pronounced corneal inflammation and neovascularization as compared to wild type littermates. Using in vivo corneal injury models, we find that MG53 promotes corneal transparency by reducing acute inflammation and post-injury vascularization. Biochemical and animal studies revealed that pyroptosis, a cytolytic cell death, is a novel pathway involved in post-injury CNV, as observed in gasdermin D, a key molecule of pyroptosis, knockout corneas which were resistant to injury-induced CNV. Further, MG53 can inhibit pyroptosis by interacting with gasdermin D, preventing its activation. In vivo corneal wounding experiments revealed corneal pyroptosis followed neutrophil infiltration. Antibody depletion of neutrophils completely abolished post-injury pyroptosis, suggesting infiltrating neutrophils undergoing pyroptosis trigger secondary corneal injury and CNV. Indeed, when irradiated WT recipient mice received bone marrow (BM) transplantation from GsdmD-/- mice, they displayed enhanced corneal healing as compared to mice that received BM from WT mice. Experiments outlined in this project are centered on testing the hypothesis that neutrophil pyroptosis is a key pathway that mediates corneal inflammation and CNV following injury; MG53 can inhibit pyroptosis via preventing activation of GasdmD, thus rhMG53 can be used as an effective means to treat corneal injury. We envision that MG53 can be applied to promote corneal healing and prevent neovascularization after injury. The outcome of this research shall have significant translational value in developing potentially effective therapies to treat corneal injury and neovascularization associated with corneal disease.

项目摘要健康的角膜是一种血管组织，是光学清晰度和良好视力的必要条件。疾病角膜的光学清晰度丢失是世界范围内第三大最常见的盲目原因。各种疾病疾病，例如角膜损伤，可能导致炎症和病理生长血管进入角膜，这是一种称为角膜新血管形成（CNV）的过程。预防血管在维持角膜的健康和透明度上必须扎根。我们以前有证明MG53是组织修复基因，可以促进两个上皮的角膜伤口愈合和基质。我们最近发现MG53可以调节角膜炎症和血管形成。一个可以在功能上靶向角膜伤口愈合中多个步骤的方法可能有可能显着改善了治疗结果，从而带来了新的治疗选择。 MG53存在于人类中泪膜，幽默和角膜上皮细胞支持其在角膜稳态中的潜在功能和伤口愈合。我们表明，MG53的遗传消融导致明显的角膜炎症和与野生型同窝仔相比，新血管化。使用体内角膜损伤模型，我们发现MG53 通过减少急性炎症和伤害后血管形成来促进角膜透明度。生化和动物研究表明，溶凋亡是一种细胞溶解细胞死亡，是遭受伤害后CNV的新途径，如在Gasdermin D中观察到的是抗损伤诱导的抑制角膜的关键分子，敲除角膜 CNV。此外，MG53可以通过与Gasdermin D相互作用来抑制凋亡，从而阻止其激活。体内角膜损伤实验表明，嗜中性粒细胞浸润后角膜凋亡。抗体耗竭中性粒细胞完全消除了伤害后的凋亡，表明浸润性嗜中性粒细胞正在发生凋亡触发继发性角膜损伤和CNV。确实，当辐照的WT受体小鼠接受骨髓（BM）从GSDMD - / - 小鼠中移植，与小鼠相比，它们显示出增强的角膜愈合从WT小鼠接收BM。该项目中概述的实验集中在测试以下假设：嗜中性粒细胞凋亡是一种关键途径，可在受伤后介导角膜炎症和CNV。 MG53可以通过防止激活GASDMD抑制凋亡，因此RHMG53可以用作治疗的有效手段角膜损伤。我们设想可以应用MG53来促进角膜愈合并防止新血管化受伤后。这项研究的结果在发展潜在的发展方面具有显着的翻译价值有效治疗与角膜疾病相关的角膜损伤和新血管形成的疗法。