Paradigms of Wound Healing and Fibrosis in the Eye

眼睛伤口愈合和纤维化的范例

• 批准号: 9127959
• 负责人: A. Sue Menko
• 金额: $ 43.36万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127959
• 关键词: Adolescent; Adult; Anterior; Apoptosis; Blindness; Cataract; Cataract Extraction; Cell Line; Cell physiology; Cells; Cicatrix; Collagen; Complex; Cornea; Corneal Injury; Data; Deposition; Disease; Disease model; Elements; Embryo; Epithelial; Epithelial Cells; Epithelium; Etiology; Eye; Fibronectins; Fibrosis; Funding; Goals; Health; Homeostasis; Image; Immune; Immunologic Surveillance; Impaired wound healing; Infectious Agent; Injury; Integrins; Knowledge; Lens Fiber; Lens development; Leukocytes; Life; Light; Liver; Macular Hole; Mediating; Membrane; Mesenchymal; Mesenchymal Stem Cells; Mesoderm Cell; Modeling; Movement; Mus; Myofibroblast; PTPRC gene; Phenotype; Play; Population; Process; Property; Protein Isoforms; Publishing; Quality of life; Recruitment Activity; Resolution; Retina; Role; Scleroderma; Shapes; Signal Transduction; Source; Stratified Squamous Epithelium; Surface; Surface Ectoderm; Tenascin; Time; Tissues; Vision; Visual impairment; Water; Wound Healing; capsule; cell motility; cell type; corneal scar; cytokine; fiber cell; injured; integrin alpha9; lens; lens capsule; lens transparency; leukocyte activation; migration; novel; prevent; repaired; response; response to injury; tissue regeneration; tissue repair; wound

DESCRIPTION (provided by applicant): Fibrosis reduces the quality of life for millions and negatively impacts vision in the cornea by causing haze and scarring, in the lens by causing Posterior Capsular Opacification (PCO), and in the retina by causing fibrovascular membrane contraction leading to macular holes. During the previous funding period we showed that in the mouse and chick lens, as in the cornea, there is an innate population of mesodermal cells that are CD45+ and that these cells go to the leading edge of an injured lens epithelium to regulate migration of the epithelium to repair the wound in a mock cataract surgery model. This same population can be induced to express α-SMA, acquiring a myofibroblast phenotype associated with causing PCO. The fact that these innate repair cells express CD45 suggests they are leukocytes. Because the lens was believed to consist exclusively of ectodermally derived cells, these data change our fundamental understanding of the lens and how it is formed and maintained. In this proposal, we propose to: 1) Establish that the lens contains a diverse resident population of mesodermally derived leukocytes with tissue specific properties, by identifying the leukocyte type(s) present in the lens and cornea that modulate the repair process following injury to ocular epithelia, examining how leukocytes impact the rate of epithelial sheet movement and the reestablishment of a normal epithelium following wounding of the lens and cornea, assessing the ability of injury-induced cytokines to mediate lens leukocyte activation, determining whether immune surveillance is induced in the lens following injury to other ocular tissues, and investigating the hypothesis that lens leukocyte activation in response to injury can recruit leukocytes from the outside the lens. 2) Establish that integrin-matrix signaling converts resident immune cells in the lens and cornea to myofibroblasts by investigating the role played by tenascin-C in the provisional matrix needed for FN(EDA+) expression and assembly, examining the mechanism by which FN(EDA+) signals myofibroblast differentiation, determining the mechanism by which α9 integrin mediates myofibroblast differentiation, investigating whether collagen assembly and stiffening modulate persistence of the myofibroblast phenotype in the lens. Leukocyte integrins are known to mediate immune cell migration after injury and leukocytes can convert into α-SMA expressing myofibroblasts. The proposed studies use well-characterized lens and cornea models to study myofibroblast formation and persistence from innate leukocytes with the goal of developing new treatments that induce myofibroblasts to revert into non-pathologic cells and or to undergo apoptosis to reduce the burden of scarring diseases in vision.

描述（由申请人提供）：纤维化降低了数百万人的生活质量，并通过引起混浊和瘢痕形成对角膜视力、通过引起后囊膜混浊（PCO）对透镜视力以及通过引起纤维血管膜收缩导致黄斑裂孔对视网膜视力产生负面影响。在之前的资助期间，我们发现在小鼠和鸡的透镜中，与角膜中一样，存在先天性CD 45+中胚层细胞群，并且这些细胞进入受损透镜上皮的前缘，以调节上皮的迁移，从而在模拟白内障手术模型中修复伤口。该相同群体可被诱导表达α-SMA，获得与引起PCO相关的肌成纤维细胞表型。这些先天性修复细胞表达CD 45的事实表明它们是白细胞。因为透镜被认为是由外胚层来源的细胞，这些数据改变了我们的基本理解的透镜，它是如何形成和维持。在本提案中，我们建议：1）确定透镜包含不同的 通过鉴定存在于透镜和角膜中的调节眼上皮损伤后修复过程的白细胞类型，检查白细胞如何影响上皮片移动的速率和透镜和角膜受伤后正常上皮的重建，评估损伤诱导的细胞因子介导透镜白细胞活化的能力，确定在其它眼组织损伤后是否在透镜中诱导免疫监视，并研究响应于损伤的透镜白细胞活化可从透镜外部募集白细胞的假设。2)通过研究腱生蛋白-C在FN（EDA+）表达和组装所需的临时基质中发挥的作用，检查FN（EDA+）信号传导肌成纤维细胞分化的机制，确定α9整联蛋白介导肌成纤维细胞分化的机制，研究胶原蛋白组装和硬化是否调节透镜中肌成纤维细胞表型的持久性。已知白细胞整联蛋白介导损伤后的免疫细胞迁移，并且白细胞可转化为表达α-SMA的肌成纤维细胞。拟定的研究使用充分表征的透镜和角膜模型来研究肌成纤维细胞形成和先天性白细胞的持续性，目的是开发新的治疗方法，诱导肌成纤维细胞恢复为非病理性细胞和/或进行细胞凋亡，以减少视觉中瘢痕形成疾病的负担。