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）

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