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（由适用提供）：纤维化通过引起镜头后囊囊无粘液化（PCO）和视网膜来降低了数百万的生活质量，并通过引起镜头来影响角膜的视力，并通过造成纤维血管膜膜的收缩而导致黄斑孔。在上一个资金期间，我们表明，在小鼠和鸡透镜中，如在角膜中，有固有的中胚层细胞群为CD45+，并且这些细胞进入受伤的透镜上皮的前缘，以调节上皮细胞的迁移，以修复模仿手术模型中的伤口。可以诱导同一种群表达α-SMA，从而获得与引起PCO相关的肌纤维细胞表型。这些先天修复细胞表达CD45的事实表明它们是白细胞。由于认为镜头始终仅是外胚层衍生的细胞，因此这些数据改变了我们对晶状体及其形成和维护的基本理解。在此提案中，我们建议：1）确定镜头包含潜水员 通过确定晶状体和角膜中存在的白细胞类型的居民中源性白细胞具有具有组织特定特性介导晶状体白细胞激活，确定在其他眼组织损伤后是否诱导透镜中诱导免疫监测，并研究了透镜白细胞激活对损伤的透镜白细胞激活可以募集透镜外部的白细胞。 2）确定整联蛋白 - 矩阵信号传导通过研究Tenascin-c在FN（EDA+）表达所需的临时基质中所扮演的作用来转化镜头和角膜的居民免疫细胞，从而转化为肌成纤维细胞，从而调查了FN（EDA+）的机制，从而确定了肌动蛋白的差异化机制，从而确定了肌动蛋白的差异化，从而确定了肌动物的差异化，从而确定了肌动物的差异。研究胶原蛋白组装和加强晶状体中成肌纤维细胞表型的持久性。损伤后培养基免疫细胞迁移已知白细胞整合素，白细胞可以转化为表达肌纤维细胞的α-SMA。拟议的研究使用特征良好的镜头和角膜模型来研究天生白细胞的肌成纤维细胞形成和持久性，目的是开发新的治疗方法，诱导肌纤维细胞诱导非病理细胞，或者或或者恢复到凋亡中以减少视力中疤痕疾病的燃烧。