MATRIX REGULATION OF CELL FUNCTION DURING WOUND HEALING

伤口愈合过程中细胞功能的基质调节

• 批准号: 2750176
• 负责人: LIVINGSTON VAN DE WATER
• 金额: $ 17.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750176
• 关键词: actins; cell migration; cell proliferation; chimeric proteins; fibroblasts; fibronectins; gene induction /repression; intermolecular interaction; protein structure function; site directed mutagenesis; tissue /cell culture; wound healing

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.

描述：(改编自申请人的摘要)伤口疤痕形成和 肌挛缩症是一种重要的临床问题，具有潜在的严重性。 对外科手术或烧伤患者的后果，包括损害 正常的组织再生和邻近组织的功能。伤痕累累 这是正常伤口愈合的一个标志，发生在细微的 成纤维细胞细胞因子、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 伤痕累累。纤维连接蛋白(FN)在大多数正常人群中水平较低 组织是介导重要功能的粘附性糖蛋白，在 体外，如细胞的激活、增殖和迁移。这个 研究人员证明，FNS水平的戏剧性增加 发生在伤口处，首先是血浆Fn从血液中渗出， 然后由伤口细胞合成，使FN成为突出的成分 伤口的母体。两个可选的拼接段，称为EIIIA或 包括在某些FN变体中的EIIIB在FN中显著表达 存在于胚胎发育过程中。正常情况下，这两个部分缺失 血浆Fn和低水平存在于大多数正常成人组织中。他们 发现包括EIIIA的FN变体的创伤细胞的表达 和EIIIB片段在损伤后显著上调 具有时间和空间特征的模式。此外，平行模式的 皮肤创面愈合过程中存在EIIIA+FN和SMCα-肌动蛋白的表达。 这些发现表明，含有FN的伤口基质提供了 在调控伤口细胞功能中的关键调节作用。事实上，当 体外测试，包括EIIIA片段的FN变体激活 成纤维细胞表达增加的SMCα-肌动蛋白。具体的 本提案的假设指出，成纤维细胞与 FN的EIIIA片段提供了一个关键信号，它与细胞因子一起 像转化生长因子-b一样，在瘢痕形成过程中调节成纤维细胞的活动。二 提出了检验这一假说的具体目标：(1)确定 EIIIA+FN中调节成纤维细胞功能的结构特征； (2)分析EIIIA+FNS对成纤维细胞功能的影响。