THROMBIN PEPTIDES REGULATING WOUND HEALING

凝血酶肽调节伤口愈合

• 批准号: 2185046
• 负责人: Darrell H. Carney
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2185046
• 关键词: biological models; cell growth regulation; cytokine; inflammation; laboratory mouse; laboratory rat; nucleic acid biosynthesis; receptor; receptor expression; synthetic peptide; thrombin; tissue /cell culture; wound healing

There is great interest in the possible use of growth factors to accelerate healing of wounds in normal and healing-impaired individuals. Yet, even with high doses and prolonged exposure, many of these factors have minimal efficacy. Thrombin, appears to be a natural initiator of tissue response to injury, causing clot formation, vascular changes, and direct migratory and mitogenic effects on cells. We have discovered that a single topical application of thrombin or the synthetic thrombin receptor-activating peptide, TRAP-508 accelerates healing of full dermal wounds in normal rats and mice, steroid-treated rats, and in genetically diabetic db+/db+ mice. TRAP-508 increases incisional breaking strength up to 80%, accelerating healing by ~4.5 days (1), and enhances closure of open wounds 50 to 100% over than seen in controls. We believe this enhancement reflects an augmentation of signals normally responsible for initiating wound healing. Our objective is to define the cellular and molecular mechanisms by which thrombin and TRAP-508 accelerate wound healing. TRAP-508 is rapidly cleared from wounds, yet it increases leukocyte recruitment, fibroblast proliferation, epithelial cell migration, and vascularization. We will determine effects of thrombin and TRAP-508 on these cells in culture and the mechanisms by which they are initiated. To establish causal relationships between in vitro and in vivo effects, we will determine if receptor antagonists, proteolytic inhibitors, anti-receptor antibodies, or antibodies to cell specific molecules can negate the enhancement of wound healing in animal models. We will also test TRAP-508 in animals depleted of inflammatory cells by antibody treatment. If these treatments negate TRAP effects, specific cell populations will be reintroduced to determine which is responsible for TRAP enhancement. Polyvinyl alcohol sponge implants will be used to measure TRAP effects on specific cells in vivo. Measurements will include: DNA synthesis; matrix deposition; changes in thrombin receptor expression; and synthesis of specific cytokines that may influence later healing events. These studies will define mechanisms by which thrombin and TRAP initiate wound healing. Understanding these mechanisms may lead to better management of chronic wounds and acceleration of healing after surgery or traumatic injury.

人们对使用增长因子的可能性非常感兴趣 加速正常和愈合受损的人的伤口愈合。 然而，即使是高剂量和长时间暴露，这些因素中的许多 疗效微乎其微。凝血酶，似乎是一种天然的引发剂 组织对损伤的反应，导致血栓形成，血管改变，以及 对细胞的直接迁移和有丝分裂作用。我们发现， 单次局部应用凝血酶或合成凝血酶 受体激活肽TRAP-508加速全真皮愈合 正常大鼠和小鼠、类固醇治疗的大鼠和遗传性大鼠的创伤 糖尿病db+/db+小鼠。TRAP-508提高切割断裂强度 高达80%，加速愈合约4.5天(1)，并增强闭合性 开放性伤口的发生率比对照组高50%到100%。我们相信这一点 增强反映了信号的增强，通常负责 开始伤口愈合。 我们的目标是定义细胞和分子机制，通过它 凝血酶和TRAP-508加速伤口愈合。Trap-508正在迅速 清除了伤口，但它增加了白细胞的募集，成纤维细胞 增殖、上皮细胞迁移和血管形成。我们会 测定凝血酶和TRAP-508对体外培养的这些细胞的影响 启动它们的机制。确定因果关系 体外和体内效应之间的关系，我们将确定 受体拮抗剂，蛋白水解物，抗受体抗体， 或者针对细胞特定分子的抗体可以抵消这种增强作用 动物模型中的伤口愈合。我们还将在动物身上测试TRAP-508 通过抗体治疗耗尽炎性细胞。如果这些 治疗抵消了陷阱效应，特定的细胞群体将 重新引入，以确定谁负责增强圈闭。 将使用聚乙烯醇海绵植入物来测量诱捕效果 在体内的特定细胞上。测量将包括：DNA合成； 基质沉积；凝血酶受体表达的变化；合成 可能会影响后来的愈合事件的特定细胞因子。这些 研究将确定凝血酶和TRAP启动伤口的机制 治愈。了解这些机制可能会带来更好的管理 慢性伤口和手术后或创伤后加速愈合 受伤。