Hydrogel encapsulation of a tissue repair protein to treat chronic wounds

水凝胶封装组织修复蛋白治疗慢性伤口

• 批准号: 10251845
• 负责人: Jianjun Guan
• 金额: $ 47.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251845
• 关键词: Ablation; Acids; Address; Anatomy; Area; Biological; Biological Process; Biology; Biomedical Research; Blood Circulation; Body Temperature; Care given by nurses; Cell membrane; Cellular Structures; Chemistry; Chronic; Cicatrix; Clinical Research; Coagulation Process; Development; Diabetes Mellitus; Disease; Drug Kinetics; Elderly; Encapsulated; Environment; Epidermis; Family suidae; Fibroblasts; Formulation; Foundations; Functional disorder; Future; Gel; Genes; Goals; Half-Life; Health Care Costs; Heart; Human; Hydrogels; Incidence; Inflammation; Inflammatory Response; Injections; Injury; Kidney; Knowledge; Link; Liquid substance; Longevity; Mediating; Membrane; Miniature Swine; Mus; Muscle; Names; Natural regeneration; Normal tissue morphology; Obesity; Organ; Pathologic; Pathology; Phase; Physiology; Polymers; Population; Process; Production; Property; Protein Family; Proteins; Public Health; Rattus; Recombinants; Research Personnel; Role; Safety; Series; Site; Skin; Skin injury; Skin wound healing; System; TRIM Family; Temperature; Testing; Therapeutic; Therapeutic Agents; Tissues; Topical application; Transgenic Mice; Treatment Efficacy; Vesicle; Wild Type Mouse; Wound models; aging population; base; chronic ulcer; chronic wound; effective therapy; epithelial stem cell; extracellular; healing; keratinocyte; migration; mouse model; non-healing wounds; novel; poly-N-isopropylacrylamide; porcine model; pre-clinical; prevent; repaired; response; scale up; skin wound; stem cell function; stem cells; tissue repair; trafficking; wound; wound care; wound closure; wound healing

PROJECT SUMMARY Wound care is a major challenge to the public health, and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of disease such as diabetes and obesity that contribute to poor wound healing. While multiple factors may contribute to complications associated with wound healing, compromised tissue repair represents an underlying cause for non-healing wounds. A recent series of studies by the investigator’s team identified a novel TRIM family protein named MG53 as an essential component of the cell membrane repair machinery. Here we provide evidence that MG53 is a vital component of wound healing and that topical application of recombinant human (rh)MG53 protein has potential to promote healing of chronic wounds. MG53 is capable of nucleating the membrane repair machinery in keratinocytes, therefore protecting injuries to the epidermis. MG53 present in the extracellular solution can facilitate migration of fibroblasts in response to scratch wounding, thus contributing to efficient reepithelization of wound closure. Moreover, we made a novel finding that links circulating MG53 to the engagement of epithelial stem cells during the chronic and remodeling phase of wound closure. While epithelial stem cells do not express endogenous MG53 protein, they can take up MG53 from circulation in response to dermal injury. Therapeutic efficacy of rhMG53 will depend on the formulation as well as the approaches of delivering MG53. Direct administration of MG53 to the wound site and indirect delivery by intravascular injection are possible approaches, but will have low efficacy due to the short half-life of MG53 in blood circulation. It is important that we develop a proper formulation for sustained delivery of rhMG53 to the wound site in order to enhance therapeutic efficacy. The goal of this project is to test the hypothesis that MG53 facilitates healing of chronic wounds by enhancing cell membrane repair and epithelial stem cell function, and hydrogel formulation of rhMG53 represents an effective means for dermal wound healing. Three specific aims are proposed: a) elucidate the mechanisms that underlie MG53’s function in wound healing (Aim 1); b) develop hydrogel-based delivery of rhMG53 to treat dermal wound (Aim 2); and c) conduct proof-of-concept study on rhMG53/hydrogel for chronic wound healing application (Aim 3). Fulfillment of these studies should advance our knowledge on the biology of MG53 in wound healing and lay the foundation for translational application of rhMG53 in treating chronic wounds in the elderly population.

项目摘要 伤口护理是公共卫生的主要挑战，由于增加而烧伤正在迅速增长 医疗保健成本，人口老龄化以及疾病事件（例如糖尿病和）的急剧上升 肥胖导致伤口愈合不良。虽然多种因素可能导致并发症 与伤口愈合相关，组织修复受损代表了非污染的根本原因 伤口。研究人员团队最近的一系列研究确定了一种新颖的装饰家族蛋白 MG53是细胞膜修复机械的重要组成部分。在这里，我们提供证据表明 MG53是伤口愈合的重要组成部分，是重组人（RH）MG53的局部应用 蛋白质具有促进慢性伤口愈合的潜力。 MG53能够将膜成核 在角质形成细胞中修复机械，因此保护表皮受伤。 MG53出现在 细胞外溶液可以促进成纤维细胞响应刮擦图的迁移，从而有助于 有效重新上皮闭合。此外，我们做出了一个新颖的发现，将循环MG53与 在伤口闭合的慢性和重塑阶段，上皮干细胞的参与。尽管 上皮干细胞不表达内源性MG53蛋白，它们可以从循环中占据Mg53 对真皮损伤的反应。 RHMG53的治疗效率将取决于公式以及 交付MG53的方法。将MG53直接施用到伤口部位，并通过 血管内注射是可能的方法，但由于MG53的半衰期短，效率较低 血液循环。重要的是，我们必须开发适当的公式来持续将RHMG53持续传递给 伤口部位以增强治疗。该项目的目的是检验MG53的假设 通过增强细胞膜修复和上皮干细胞功能，促进慢性逻辑逻辑的愈合，以及 RHMG53的水凝胶公式代表了皮肤伤口愈合的有效手段。三个具体目标 提出：a）阐明MG53在伤口愈合中功能的机制（AIM 1）； b）发展 基于水凝胶的RHMG53递送以治疗皮肤伤口（AIM 2）； c）进行概念验证研究 RHMG53/用于慢性伤口愈合应用的水凝胶（AIM 3）。这些研究的履行应该进步 我们在伤口愈合中对MG53生物学的了解，并为翻译应用奠定了基础 RHMG53治疗老年人口的慢性伤口。