THE ROLE OF LAMININ 5 IN DIABETIC ULCER HEALING

描述（改编自应用程序） 2000年健康人的一个既定目标是减少 糖尿病患者下肢截肢率与1988年基线相比 8.2/1000，到2000年的目标发病率为4.9/1000。尽管努力 在预防方面，截肢率继续上升， DM患者糖尿病溃疡的发病机制 需要新的治疗策略来扭转 截肢率。本申请的目的是使用新的分子 通过增加迁移促进糖尿病溃疡愈合的技术 细胞（角质形成细胞）在溃疡边缘。层粘连蛋白5（Lam 5） 细胞信号通路是本研究的重点。一个跨学科 研究小组将在糖尿病患者和小鼠中进行拟议的实验。这 应用程序将测试三个一般假设：1。主要赤字 糖尿病溃疡的闭合是角质形成细胞迁移的失败，尽管有显著的 溃疡边缘角质形成细胞增生。2. Lam 5介导的信号传导， 在糖尿病中受损。3. 阐明Lam 5细胞信号通路将导致新的方法， 刺激角质细胞迁移和加速糖尿病溃疡愈合。为了 为了验证这些假设，我们将实现以下具体目标： 具体目标1。描述糖尿病患者的慢性溃疡特征， 关于Lam 5，来自糖尿病和正常人类受试者/小鼠的急性伤口 同种型和Lam 5 mRNA，Lam 5相关整合素α 6-β 4 α 3-β 1和增殖标记Ki 67。具体目标2。评价 Lam 5亚结构域的功能以及设计和生产重组 Lam 5的同种型。具体目标3。评估角质形成细胞 调节Lam 5的合成和沉积，并评估Lam 5在 正常和糖尿病细胞的迁移。具体目标4。评估的影响 将重组Lam 5同种型应用于db/db糖尿病患者的伤口 小鼠和开发生物材料，引起愈合率的最大增加。

DESCRIPTION (adapted from the application) One of the stated goals of Healthy People 2000 is to reduce the incidence of lower extremity amputation in diabetic patients from the 1988 baseline rate of 8.2/1000 to a target incidence of 4.9/1000 in the year 2000. Despite efforts directed at prevention, the rate of amputation has continued to rise in patients with DM. A better understanding of the pathogenesis of diabetic ulcers and novel treatment strategies are required to reverse the rising trend in the rate of amputation. The goal of this application is to use new molecular technologies to enhance healing of diabetic ulcers by increasing the migration of cells (keratinocytes) at the ulcer margin. The laminin 5 (Lam 5) cell-signaling pathway is the focus of this investigation. An interdisciplinary team will conduct the proposed experiments in patients and mice with DM. This application will test three general HYPOTHESES: 1. The principle deficit in closure of diabetic ulcers is failure of keratinocyte migration despite marked keratinocyte proliferation at the ulcer margin. 2. Lam 5 mediated signaling, essential for keratinocyte migration, is impaired in diabetes mellitus. 3. Clarification of Lam 5 cellsignaling pathways will lead to novel approaches to stimulate keratinocyte migration and speed healing of diabetic ulcers. In order to test these hypotheses we will carry out the following Specific Aims: Specific Aim 1. Characterize chronic ulcers from patients with diabetes and acute wounds from diabetic and normal human subjects/mice regarding Lam 5 isoforms and Lam 5 mRNA, the Lam 5 associated integrins alpha6-beta4 alpha3-beta1 and the proliferation marker Ki67. Specific Aim 2. Evaluate functions for Lam 5 sub-domains as well as design and produce recombinant isoforms of Lam 5. Specific Aim 3. Evaluate mechanisms by which keratinocytes regulate synthesis and deposition of Lam 5, and evaluate the role of Lam 5 in the migration of normal and diabetic cells. Specific Aim 4. Assess the effects of application of recombinant Lam 5 isoforms to the wounds of db/db diabetic mice and develop bioniaterials that elicit a maximal increase in healing rate.