Keratocyte regulation in corneal repair

描述（由申请人提供）：我们目前的目标是研究CCN 2（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的分泌蛋白已被分类为生长因子和基质细胞组分，其合成和分泌受TGF-β刺激。它在创伤后的角膜基质和其他结缔组织中高度表达。在模拟角膜伤口愈合的细胞培养模型中，除了38 kDa CCN 2之外，我们还免疫检测了先前未描述的31 kDa蛋白（31 kDa CCN 2）。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 CCN 2诱导的，而分化和纤维化是由31 kDa形式的CCN 2诱导的。测试我们工作模型的具体目的如下：1.检验基质信号影响TGF-3诱导和CCN 2加工的假设。2.测试基质和31 kDa CCN 2的组合信号传导稳定局灶性粘连并促进肌成纤维细胞分化的假设3。检验以下假设：归因于CCN 2的一些高度不同的信号（包括迁移、增殖、基质合成或肌成纤维细胞分化）分布于38 kDa和31 kDa CCN 2。最近的研究表明，LASIK手术后，人的角膜不会“愈合”。中心区域具有长时间的细胞减少（没有细胞），而切口部位纤维化，具有丰富的肌成纤维细胞和基质。作为我们工作模型的必然结果，如果抑制CCN 2的局部和特异性蛋白水解，则可以刺激角膜成纤维细胞迁移到伤口中以促进健康修复。这种抑制还可以防止肌成纤维细胞形成和局部纤维化。

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.