THE ROLE OF LAMININ 5 IN DIABETIC ULCER HEALING

层粘连蛋白 5 在糖尿病溃疡愈合中的作用

• 批准号: 6789928
• 负责人: JOHN Everett OLERUD
• 金额: $ 49.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789928
• 关键词: biomaterial development /preparation; clinical research; diabetes mellitus; diabetes mellitus therapy; human subject; integrins; keratinocyte; laboratory mouse; laminin; medical complication; nonhuman therapy evaluation; protein engineering; protein isoforms; protein structure function; recombinant proteins; ulcer; wound healing

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.

描述（改编自应用程序） 《健康人 2000》的既定目标之一是减少以下疾病的发生率： 与 1988 年基线相比，糖尿病患者下肢截肢率 8.2/1000 到 2000 年目标发病率为 4.9/1000。尽管做出了努力 为了预防，截肢率持续上升 糖尿病患者。更好地了解糖尿病溃疡的发病机制 需要新的治疗策略来扭转发病率上升的趋势 截肢率。该应用的目标是使用新的分子 通过增加迁移来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) 细胞信号通路是本次研究的重点。跨学科 研究小组将在糖尿病患者和小鼠身上进行拟议的实验。这 应用程序将测试三个一般假设： 1. 的主要赤字 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 溃疡边缘角质细胞增生。 2. Lam 5介导的信号传导， 对于角质形成细胞迁移至关重要，但在糖尿病中受损。 3. Lam 5 细胞信号通路的阐明将带来新的方法 刺激角质形成细胞迁移并加速糖尿病溃疡的愈合。为了 为了检验这些假设，我们将实现以下具体目标： 具体目标 1. 表征糖尿病患者的慢性溃疡和 糖尿病和正常人类受试者/小鼠与 Lam 5 相关的急性伤口 同种型和 Lam 5 mRNA，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 子结构域的功能以及设计和生产重组体 Lam 亚型 5. 具体目标 3. 评估角质形成细胞的机制 调节 Lam 5 的合成和沉积，并评估 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糖尿病创面中的应用 小鼠并开发出可最大程度提高治愈率的生物材料。

项目成果

Epidermal and dermal integration into sphere-templated porous poly(2-hydroxyethyl methacrylate) implants in mice.

• DOI: 10.1002/jbm.a.32798
• 发表时间: 2010-09-15
• 期刊: JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
• 影响因子: 4.9
• 作者: Fukano, Y.;Usui, M. L.;Underwood, R. A.;Isenhath, S.;Marshall, A. J.;Hauch, K. D.;Ratner, B. D.;Olerud, J. E.;Fleckman, P.
• 通讯作者: Fleckman, P.

Ultrastructural localization of integrin subunits beta4 and alpha3 within the migrating epithelial tongue of in vivo human wounds.

整合素亚基β4和α3在体内人类伤口迁移上皮舌内的超微结构定位。

• DOI: 10.1369/jhc.2008.952176
• 发表时间: 2009
• 期刊: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
• 作者: Underwood,RobertA;Carter,WilliamG;Usui,MarciaL;Olerud,JohnE
• 通讯作者: Olerud,JohnE