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Carbon monoxide-releasing molecules as therapeutic agents to promote wound healing

释放一氧化碳的分子作为促进伤口愈合的治疗剂

基本信息

批准号：
284059745
负责人：
Professor Dr. Ulrich Schatzschneider
金额：
--
依托单位：
Institut für Anorganische Chemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/284059745?language=en
关键词：
Carbon monoxide releasing molecules therapeutic

项目摘要

Chronic wounds are a major healthcare problem associated with high hospitalization costs and morbidity, in particular in diabetic patients. Apart from wound dressings and antibiotics, there is presently very limited choice when deciding which drug therapy to employ for promoting wound repair. Normally, wound healing consists of three overlapping phases that include inflammation, new blood vessel formation, and tissue remodelling. Emerging findings reveal that activation of heme oxygenase-1 (HO-1) might be a very relevant pathway in the context of wound healing. This enzyme degrades heme to iron, biliverdin and carbon monoxide (CO), a ubiquitous signalling molecule necessary for cells to counteract oxidative stress and injury. Corroborating evidence indicates that the HO-1/CO pathway is essential in the restoration of cellular homeostasis and thus may have an important role in healing and repair processes. HO-1 has been found to be highly expressed in the skin after wounding and treatment with an HO-1 inhibitor delayed wound closure. In contrast, mice over-expressing HO-1 in keratinocytes displayed an improved neovascularisation and accelerated wound healing. The advent of CO-releasing molecules (CORMs), a class of compounds that deliver precise amounts of CO to tissues and exerting beneficial and anti-inflammatory effects, provides a very promising technology for the therapeutic exploitation of CO in this disorder. Here we propose a comprehensive research approach that focuses on two major areas, namely the synthesis and optimization of novel photoactivable CORMs and CORMs nanomaterials for topical applications and studies on the pro-healing actions of these systems in vitro and in vivo. We will synthesize and characterize new CORMs that are triggered by low-energy red light to release CO as well as CORM nanomaterials that will maximize the delivery, efficacy and specificity of CO. We want to study the effect of these systems in modulating processes relevant to wound healing such as keratinocytes/fibroblast proliferation and migration, angiogenic activity of endothelial cells, and inflammation in macrophages. The efficacy of these novel CORMs will also be assessed in diabetes-like conditions. The most promising CORMs will be tested in vivo as novel topical agents to stimulate wound healing in normal and diabetic mice. The multidisciplinary nature and the expertise of the partners in chemistry, cell biology and pharmacology clearly represent the strength and added value of this project. The topical use of CORMs specifically tailored for the treatment of wounds is a novel technological approach and the major task of the project. The two partners are well-recognized leaders in Europe and possess all know-how necessary for the success of this research project. Thus, their international collaboration not only represents an added value but a true competitive advantage to advance therapeutic application of CORMs.

慢性伤口是与高住院费用和发病率相关的主要医疗保健问题，特别是在糖尿病患者中。除了伤口敷料和抗生素外，目前在决定采用哪种药物治疗来促进伤口修复时，选择非常有限。通常，伤口愈合包括三个重叠的阶段，包括炎症，新血管形成和组织重塑。新的研究结果表明，血红素氧合酶-1（HO-1）的激活可能是伤口愈合过程中一个非常相关的途径。这种酶将血红素降解为铁、胆绿素和一氧化碳（CO），一氧化碳是细胞对抗氧化应激和损伤所必需的普遍存在的信号分子。确凿的证据表明，HO-1/CO途径是必不可少的细胞内稳态的恢复，因此可能在愈合和修复过程中发挥重要作用。已经发现HO-1在创伤后的皮肤中高度表达，并且用HO-1抑制剂治疗延迟了创伤闭合。相比之下，在角质形成细胞中过表达HO-1的小鼠显示出改善的新生血管形成和加速的伤口愈合。CO释放分子（CORM）是一类向组织递送精确量的CO并发挥有益和抗炎作用的化合物，其出现为CO在这种疾病中的治疗开发提供了非常有前途的技术。在这里，我们提出了一个全面的研究方法，侧重于两个主要领域，即合成和优化的新型光活化的CORM和CORM纳米材料的局部应用和研究这些系统在体外和体内的促愈合作用。我们将合成和表征由低能量红光触发以释放CO的新CORM以及CORM纳米材料，这些材料将最大限度地提高CO的递送，功效和特异性。我们希望研究这些系统在调节与伤口愈合相关的过程中的作用，如角质形成细胞/成纤维细胞增殖和迁移，内皮细胞的血管生成活性，以及巨噬细胞中的炎症。还将在糖尿病样病症中评估这些新型CORM的功效。最有前途的CORM将在体内测试作为新的局部药物，以刺激正常和糖尿病小鼠的伤口愈合。多学科性质和合作伙伴在化学，细胞生物学和药理学方面的专业知识清楚地代表了该项目的优势和附加值。局部使用专门为伤口治疗定制的CORM是一种新的技术方法，也是该项目的主要任务。这两个合作伙伴是欧洲公认的领导者，拥有成功完成该研究项目所需的所有专业知识。因此，他们的国际合作不仅代表了附加值，而且是推进CORM治疗应用的真正竞争优势。