MATRIX REGULATION OF CELL FUNCTION DURING WOUND HEALING

描述：（改编自申请人摘要）伤口瘢痕和 挛缩是一个重要的临床问题， 手术或烧伤患者的后果，包括 正常组织再生和邻近组织功能。 疤痕 这是正常伤口愈合的标志， 调节成纤维细胞因子，生长因子， 蛋白酶和细胞外基质分子。 长期目标是 了解这种调节机制，并开发新的治疗方法来控制 疤痕 纤维连接蛋白（FN），在大多数正常人中以低水平存在， 组织，是介导重要功能的粘附糖蛋白， 体外，如细胞活化，增殖和迁移。 的 研究人员证明，FN水平的急剧增加 发生在伤口部位，首先是血浆FN从血液中外渗， 然后由伤口细胞合成，使FN成为主要成分， 伤口的组织结构 两个可变剪接片段，称为EIIIA或 包括在某些FN变体中的EIIIB在FN中显著表达， 存在于胚胎发生过程中。 这两个节段是正常缺失的 血浆FN，并且在大多数正常成人组织中以低水平存在。 他们 发现伤口细胞表达FN变体，包括EIIIA 和EIIIB片段在损伤后显著上调， 空间和时间模式。 此外， EIIIA+ FN和SMC α-肌动蛋白表达发生在皮肤伤口愈合期间。 这些发现表明，含FN的伤口基质提供了一个 在控制伤口细胞功能中的关键调节功能。 其实，当 在体外测试中，包括EIIIA片段的FN变体激活 成纤维细胞表达增加水平的SMC α-肌动蛋白。 具体 本提案的假设指出，成纤维细胞粘附于 FN的EIIIA片段提供关键信号，其与细胞因子一起 与TGF-β一样，在瘢痕形成过程中调节成纤维细胞的活性。 两 提出了具体的目标来检验这一假设：（1）确定 调节成纤维细胞功能的EIIIA+ FN内的结构特征; (2)分析EIIIA+ FN调控的特异性成纤维细胞功能。

DESCRIPTION: (Adapted from the applicant's abstract) Wound scarring and contracture is an important clinical problem with potentially serious consequences for the surgical or burn patient, including impairment of normal tissue regeneration and neighboring tissue function. The scarring that is a hallmark of normal wound healing occurs as a consequence of finely regulated interactions between fibroblasts cytokines, growth factors, proteases and extracellular matrix molecules. The long term goal is to understand this regulatory mechanism and develop new therapies to control scarring. The fibronectins (FNs), present in low levels in most normal tissues, are adhesive glycoproteins that mediate important functions, in vitro, such as cell activation, proliferation and migration. The investigators demonstrate that a dramatic increase in the levels of FNs occurs at the wound site, first by extravasation of plasma FN from blood, and then from synthesis by wound cells, making FNs as prominent components of the wound matrix. Two alternatively spliced segments, termed EIIIA or EIIIB, included in certain FN variants are expressed prominently in FNs present during embryogenesis. These two segments are missing from normal plasma FN and are present at low levels in most normal adult tissues. They find that expression by wound cells of FN variants that include the EIIIA and EIIIB segments is dramatically upregulated following injury in a characteristic spatial and temporal pattern. Moreover, parallel patterns of EIIIA+FNs and SMC a-actin expression occur during cutaneous wound healing. These findings suggest that the FN-containing wound matrix supplies a critical regulatory function in governing wound cell function. Indeed, when tested in vitro, FN variants that include the EIIIA segment activate fibroblasts to express increased levels of SMC a-actin. The specific hypothesis of the present proposal states that adhesion of fibroblasts to the EIIIA segment of FN provides a key signal, which together with cytokines like TGF-b, regulate the activity of fibroblasts during scar formation. Two specific aims are proposed to test this hypothesis: (1) To determine the structural features within EIIIA+FNs that regulate fibroblasts functions; (2) To analyze specific fibroblast functions regulated by EIIIA+FNs.