Regulation of Corneal Repair by Metalloproteinases

金属蛋白酶对角膜修复的调节

• 批准号: 8579237
• 负责人: Matilda F Chan
• 金额: $ 39.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579237
• 关键词: Address; Affect; Biological Assay; Blindness; CCL2 gene; Cells; Cicatrix; Clinical; Collaborations; Confocal Microscopy; Cornea; Corneal Injury; Corneal Neovascularization; Data; Family; Fibrosis; Flow Cytometry; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Keratoplasty; Laser Surgery; Lead; Maintenance; Matrix Metalloproteinases; Measures; Mediating; Medical; Metalloproteases; Modality; Modeling; Molecular; Mus; Myofibroblast; Pathology; Patients; Penetrating Keratoplasty; Peptide Hydrolases; Process; Proteolysis; Protocols documentation; Regulation; Research; Research Proposals; Role; Sampling; Therapeutic; Thick; Time; Tissues; Trauma; Ulcer; VEGFA gene; Vision; Wound Healing; angiogenesis; chemokine; corneal repair; corneal scar; in vivo; injured; insight; macrophage; matrix metalloproteinase 12; neovascular; neovascularization; novel; prevent; protective effect; public health relevance; repaired; research study; response; response to injury; translational approach

PROJECT SUMMARY Corneal opacification affects millions of people and is the second leading cause of blindness in the world. The effective medical treatment of vision-threatening corneal opacification is a major unmet clinical challenge. Injury is a major cause of corneal opacification and can occur by a variety of mechanisms including infectious and noninfectious ulcers, incisional and laser surgery, and trauma. Following injury, proteinases regulate aspects of the repair process including inflammation, neovascularization, and remodeling. Excessive proteolysis resulting in corneal scarring has been associated with loss of corneal clarity. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with corneal wound repair in humans. It has long been appreciated that tissue destruction and corneal pathology following corneal injury is associated with excessive proteolytic activity mediated by MMPs. However, potential protective effects of MMPs in the repair response are underappreciated. We have found that MMP12 (macrophage metalloelastase) is expressed in injured corneas and has a protective effect on corneal fibrosis during wound repair. Our preliminary data show that MMP12 protects against corneal stromal myofibroblast transformation, that MMP12 blunts the corneal angiogenic response to injury via regulation of VEGFA expression, and that MMP12 inhibits the accumulation of macrophages in wounded corneas via regulation of CCL2 expression. Collectively, these data demonstrate a protective role of MMP12 in the fibrotic, neovascular, and inflammatory responses to corneal injury. Furthermore, our findings suggest MMP12 as an important factor needed for the maintenance of corneal clarity following injury. Given these findings, we hypothesize that MMP12 regulation of CCL2 expression is a common mechanism by which MMP12 inhibits inflammation and neovascularization. This hypothesis will be addressed in the experiments of the following Specific Aims: (1) to define the role of MMP12 in the regulation of expression of CCL2 and CCR2; (2) to determine the interplay of MMP12 and CCL2 in the regulation of corneal neovascularization; and (3) to characterize MMP12 expression and activity levels in patient corneal samples. This combination of molecular and translational approaches will provide novel insight into the mechanisms by which MMP12 protects against corneal fibrosis and will open the possibility of developing novel modalities aimed at preventing and treating pathological fibrosis in human patients.

项目摘要 角膜混浊影响数百万人，是世界上第二大致盲原因。的 对威胁视力的角膜混浊进行有效的医学治疗是一个主要的尚未解决的临床挑战。 损伤是角膜混浊的主要原因，可通过多种机制发生，包括感染性角膜混浊。 和非感染性溃疡、切口和激光手术以及创伤。损伤后，蛋白酶调节 修复过程的各个方面，包括炎症、新血管形成和重塑。过度 导致角膜瘢痕形成的蛋白水解与角膜透明度的丧失有关。矩阵 金属蛋白酶（MMPs）是与角膜创伤相关的最重要的蛋白酶家族 修复人类。长期以来，人们已经认识到，角膜移植后的组织破坏和角膜病理学改变可能与角膜移植术后的组织破坏和角膜病理学改变有关。 损伤与MMP介导的过度蛋白水解活性有关。然而，潜在的保护作用 MMPs在修复反应中的作用被低估了。 我们发现MMP 12（巨噬细胞金属弹性蛋白酶）在受损角膜中表达， 在伤口修复过程中对角膜纤维化的保护作用。我们的初步数据显示，MMP 12可以保护 MMP 12抑制角膜基质肌成纤维细胞转化， 损伤通过调节VEGFA表达，且MMP 12抑制巨噬细胞在 通过调节CCL 2的表达来修复受伤的角膜。总的来说，这些数据表明了 MMP 12在角膜损伤的纤维化、新生血管和炎症反应中的作用此外，我们的发现 提示MMP 12是损伤后维持角膜透明度所需的重要因素。 鉴于这些发现，我们假设MMP 12对CCL 2表达的调节是一种常见的机制， MMP 12抑制炎症和新血管形成。这一假设将在 （1）确定MMP 12在调节细胞表达中的作用， CCL 2和CCR 2;（2）确定MMP 12和CCL 2在角膜上皮细胞增殖调节中的相互作用。 新血管形成;和（3）表征患者角膜样品中MMP 12的表达和活性水平。 这种分子和翻译方法的结合将提供新的见解的机制， MMP 12可以防止角膜纤维化， 旨在预防和治疗人类患者的病理性纤维化。