Keratocyte regulation in corneal repair

描述（由申请人提供）：我们目前的目标是研究CCN2（也称为结缔组织生长因子，CTGF）促进角膜伤口愈合的潜力。这种38 kDa的分泌蛋白被归类为生长因子和基质细胞成分，其合成和分泌受到TGF-3的刺激。它在角膜基质和其他结缔组织中高度表达。在模拟角膜创面愈合的细胞培养模型中，除了38 kDa CCN2外，我们还免疫检测了31 kDa蛋白（31 kDa CCN2），这是以前没有描述过的。我们的工作模型是角膜成纤维细胞增殖和迁移是由全长38 kDa的CCN2诱导的，而分化和纤维化是由31 kDa的CCN2诱导的。对我们的工作模型进行测试的具体目的如下：1。验证基质信号影响TGF-3诱导和CCN2加工的假设。2. 验证基质和31 kDa CCN2联合信号传导稳定局灶粘连并促进肌成纤维细胞分化的假设3。验证CCN2的一些高度分化信号，包括迁移、增殖、基质合成或肌成纤维细胞分化，分布在38 kDa和31 kDa的CCN2上的假设。最近的研究表明，在LASIK手术后，人类的角膜并没有“愈合”。中央区域有长时间的细胞增生（没有细胞），而切口部位有丰富的肌成纤维细胞和基质。作为我们工作模型的推论，如果抑制局部和特异性的CCN2蛋白水解，可以刺激角膜成纤维细胞向伤口迁移，促进健康修复。这种抑制也可以防止肌成纤维细胞的形成和局部纤维化。

DESCRIPTION (provided by applicant): Our current goal is to investigate the potential for CCN2 (also known as Connective Tissue Growth Factor, CTGF) to promote corneal wound healing. This 38 kDa secreted protein has been classified as both a growth factor and a matricellular component whose synthesis and secretion are stimulated by TGF-3. It is highly expressed in the corneal stroma and other connective tissues after wounding. In a cell culture model that mimics corneal wound healing, we have immunodetected in addition to the 38 kDa CCN2, the 31 kDa protein (31 kDa CCN2) that has not been previously described. Our working model is that corneal fibroblast proliferation and migration are induced by full-length 38 kDa CCN2 whereas differentiation and fibrosis are induced by the 31 kDa form of CCN2. The Specific Aims to test our working model are as follows: 1. Test the hypothesis that matrix signals influence TGF-3 induction and processing of CCN2. 2. Test the hypothesis that combinatorial signaling of matrix and 31 kDa CCN2 stabilizes focal adhesions and promotes myofibroblast differentiation 3. Test the hypothesis that some of the highly divergent signals attributed to CCN2 including migration, proliferation, matrix synthesis or myofibroblast differentiation are distributed to either 38 kDa and 31 kDa CCN2. Recent studies show that after LASIK, the human cornea does not "heal". The central region has a prolonged period of hypocellularity (absence of cells), whereas the site of the incision is fibrotic with abundant myofibroblasts and matrix. As a corollary of our working model, migration of corneal fibroblasts into a wound to promote healthy repair could be stimulated if local and specific proteolysis of CCN2 were inhibited. This inhibition could also prevent myofibroblast formation and local fibrosis.