FIBRONECTIN AND CELL RECRUITMENT

描述：(改编自申请人的摘要)-中央 这一提议的假设是，特定的整合素是需要的 皮肤中成纤维细胞的迁移和肉芽组织 伤口。皮肤损伤和皮肤损伤之间有三天的延迟 肉芽组织堆积。在这一延迟期间，成纤维细胞增加 他们的临时基质受体和减少他们的胶原蛋白受体。 作者认为富含纤维蛋白/纤维连接蛋白的临时基质是 调控成纤维细胞表达的部分诱导机制 临时基质整合素，一种调节机制，对于 创面早期愈合反应。为了检验这一假设，目标1提出了 检测成纤维细胞整合素的表达和功能 猪皮肤切除创面肉芽组织的形成 伤口范例以及人类皮肤伤口。为了证明这一要求 对于肉芽组织发育过程中整合素的调节， 整合素的表达将通过添加特定的 抗整合素抗体或环肽整合素拮抗剂 或将外源性成纤维细胞导入伤口部位。 对其特定整合素的体外调节。在目标2中，监管机构 人皮肤成纤维细胞整合素的临时控制 基质和胶原基质将在分子水平上确定 利用模拟皮肤创伤环境的体外系统。这 AIM将包括对细胞因子和细胞外基质增强剂的研究 特定整合素启动子中的元件，并鉴定 刺激这些整合素增强元件的反式激活因子。 Aim 3建议确定成纤维细胞所需的整合素 在临时基质纤维上的运动和成纤维细胞的迁移 从胶原凝胶到纤维蛋白凝块，使用的体外条件 模拟早期创伤环境中的选择性事件。为此， 整合素将受到抗体和环肽拮抗剂的调节，通过 培养条件和分子生物学操作。此外, 有人建议研究整合素如何通过以下方式促进细胞运动 特异性抑制物对成纤维细胞第二信使通路的调节 和反义寡核苷酸。

DESCRIPTION: (Adapted from the applicant's abstract) - The central hypothesis of this proposal is that specific integrins are required for fibroblast migration and granulation tissue organization in cutaneous wounds. A three day delay intervenes between cutaneous wounding and granulation tissue accumulation. During this delay fibroblasts increase their provisional matrix receptors and decrease their collagen receptors. The authors propose that the fibrin/fibronectin-rich provisional matrix is part of the induction mechanism controlling fibroblast expression of provisional matrix integrins, a regulatory mechanism that is essential for the early wound healing response. To test this hypothesis, Aim 1 proposes to determine the expression and function of fibroblasts integrins during granulation tissue development of cutaneous wounds using porcine excisional wound paradigms as well as human cutaneous wounds. To prove the requirement for the modulation of integrins during granulation tissue development, integrin expression will be experimentally regulated by addition of specific anti-integrin antibodies or cyclic peptide integrin antagonists to the wound site or by introducing exogenous fibroblasts to the wound site after in vitro modulation of their specific integrins. In Aim 2, the regulatory control of human skin fibroblast integrins in the context of provisional matrix vs collagen matrix will be determined at the molecular level utilizing in vitro systems that simulate cutaneous wound environments. This aim will include a study of cytokine and extracellular matrix enhancer elements in specific integrin promoters, and identification of transactivating factors that stimulate these integrin enhancer elements. Aim 3 proposes to determine which integrins are required for fibroblast movement over provisional matrix fibrils, and for fibroblast transmigration from collagen gels into fibrin clots, using in vitro conditions that simulate selective events in the early wound environment. To this end, integrins will be modulated by antibody and cyclic peptide antagonists, by culture conditions, and by molecular biological manipulations. In addition, it is proposed to investigate how integrins promote cell movement by modulation of fibroblast second messenger pathways using specific inhibitors and antisense oligonucleotides.