Regulation of Corneal Repair by Metalloproteinases

金属蛋白酶对角膜修复的调节

• 批准号: 8720005
• 负责人: Matilda F Chan
• 金额: $ 38.72万
• 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/8720005
• 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

DESCRIPTION (provided by applicant): 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 metalloproteinase (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.

描述(申请人提供)：角膜混浊影响数以百万计的人，是世界上第二大致盲原因。威胁视力的角膜混浊的有效治疗是临床上尚未解决的主要挑战。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、新生血管和重塑。过度的蛋白分解导致角膜瘢痕形成与角膜透明度的丧失有关。基质金属蛋白酶(MMPs)是与人类角膜创伤修复相关的最重要的蛋白酶家族。长期以来，人们认识到角膜损伤后的组织破坏和角膜病理与MMPs介导的过度蛋白分解活性有关。然而，MMPs在修复反应中的潜在保护作用被低估。我们发现MMP12(巨噬细胞金属弹性酶)在损伤的角膜中表达，并在创伤修复过程中对角膜纤维化具有保护作用。我们的初步数据显示，MMP12保护角膜基质肌成纤维细胞的转化，MMP12通过调节VEGFA的表达来钝化角膜损伤的血管生成反应，MMP12通过调节CCL2的表达来抑制损伤角膜中巨噬细胞的聚集。总的来说，这些数据显示了MMP12在角膜损伤的纤维化、新生血管和炎症反应中的保护作用。此外，我们的研究结果表明，MMP12是损伤后维持角膜透明度所需的一个重要因素。鉴于这些发现，我们假设MMP12对CCL2表达的调节是MMP12抑制炎症和新生血管的常见机制。这一假说将在以下特定目的的实验中得到解决：(1)确定MMP12在调节CCL2和CCR2表达中的作用；(2)确定MMP12和CCL2在调节角膜新生血管中的相互作用；以及(3)表征患者角膜样本中MMP12的表达和活性水平。这种分子和翻译方法的结合将为MMP12预防角膜纤维化的机制提供新的见解，并将为开发旨在预防和治疗人类患者病理性纤维化的新方法打开可能性。