Paradigms of Wound Healing and Fibrosis in the Eye

描述（由申请人提供）：纤维化降低了数百万人的生活质量，并对角膜造成雾霾和疤痕，对晶状体造成后囊膜混浊（PCO），对视网膜造成纤维血管膜收缩导致黄斑孔，对视力产生负面影响。在之前的资助期间，我们发现在小鼠和鸡晶状体中，与角膜一样，存在先天的CD45+中胚层细胞群，这些细胞进入受损晶状体上皮的前沿，调节上皮的迁移，以修复模拟白内障手术模型中的伤口。同样的群体可以诱导表达α-SMA，获得与引起PCO相关的肌成纤维细胞表型。这些先天修复细胞表达CD45的事实表明它们是白细胞。由于晶状体被认为完全由外胚层细胞组成，这些数据改变了我们对晶状体及其形成和维持方式的基本理解。在这个提案中，我们建议：1)建立镜头包含多样化

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.