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THROMBIN PEPTIDES REGULATING WOUND HEALING

凝血酶肽调节伤口愈合

基本信息

批准号：
2185047
负责人：
Darrell H. Carney
金额：
$ 18.98万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-08-01 至 1998-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2185047
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

项目摘要

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.

人们对可能利用生长因子来加速正常和愈合受损个体的伤口愈合。然而，即使是高剂量和长时间的接触，具有最小的功效。凝血酶，似乎是一种天然的引发剂，组织对损伤的反应，导致凝块形成、血管变化，以及对细胞的直接迁移和促有丝分裂作用。我们发现凝血酶或合成凝血酶的单次局部应用受体激活肽，TRAP-508加速全真皮愈合正常大鼠和小鼠、类固醇治疗大鼠和遗传性糖尿病db+/db+小鼠。 TRAP-508增加切口断裂强度高达80%，加速愈合约4.5天（1），并增强闭合比对照组多50 - 100%。我们相信这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确定细胞和分子机制，凝血酶和TRAP-508加速伤口愈合。 TRAP-508是快速从伤口中清除，但它增加了白细胞的招募，成纤维细胞增殖、上皮细胞迁移和血管形成。我们将确定凝血酶和TRAP-508对培养物中这些细胞的影响，它们被启动的机制。为了确定因果关系体外和体内效应之间的关系，我们将确定是否受体拮抗剂，蛋白水解抑制剂，抗受体抗体，或者细胞特异性分子的抗体可以抵消动物模型中的伤口愈合。我们还将在动物身上测试TRAP-508 通过抗体治疗消除炎性细胞。如果这些治疗否定了TRAP效应，特定的细胞群将被重新引入，以确定负责TRAP增强。聚乙烯醇海绵植入物将用于测量TRAP效应对体内特定细胞的作用。测量将包括：DNA合成; 基质沉积;凝血酶受体表达的变化;和合成特定的细胞因子，可能会影响以后的愈合事件。这些研究将确定凝血酶和TRAP引发创伤的机制治愈了解这些机制可能会导致更好的管理手术或创伤后的慢性伤口和加速愈合损伤