THE ROLE OF LAMININ 5 IN DIABETIC ULCER HEALING

说明(改编自应用程序) 2000年健康人大会的目标之一就是减少 糖尿病患者的下肢截肢率自1988年基线比率 到2000年，目标发病率为4.9/1000。尽管做出了努力 为了预防，截肢率在#年继续上升。 糖尿病患者。加深对糖尿病溃疡发病机制的认识 需要新的治疗策略来扭转这一上升趋势。 截肢率。这个应用的目标是使用新的分子 通过增加移行促进糖尿病溃疡愈合的技术 溃疡边缘的细胞(角质形成细胞)。层粘连蛋白5(LAM 5) 细胞信号通路是本研究的重点。跨学科的 该团队将在糖尿病患者和小鼠身上进行拟议的实验。这 申请将检验三个一般假设：1. 糖尿病溃疡的闭合是角质形成细胞迁移失败，尽管有明显的 溃疡边缘角质形成细胞增殖。2.LAM-5介导的信号转导 是角质形成细胞迁移所必需的，在糖尿病中受损。3. LAM 5细胞信号通路的阐明将导致新的方法 刺激角质形成细胞迁移，加速糖尿病溃疡愈合。按顺序 为了验证这些假设，我们将实现以下具体目标： 具体目标1.确定糖尿病患者的慢性溃疡的特征 糖尿病和正常人/小鼠对LAM-5的急性创伤 异构体和LAM 5mRNA，LAM 5相关整合素α6-β4 α3-β1和增殖标记Ki67。具体目标2.评估 LAM 5亚域的功能以及设计和生产重组 LAM亚型5.特异性靶点3.评价角质形成细胞 调节LAM-5的合成和沉积，并评价LAM-5在 正常细胞和糖尿病细胞的迁移。具体目标4.评估效果 重组LAM-5亚型在db/db糖尿病创面的应用 并开发出可最大限度提高治愈率的生物材料。

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.