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面临的重大挑战，并且由于日益增加的医疗费用，负担正在迅速增加 医疗保健费用，人口老龄化和糖尿病等疾病发病率的急剧上升， 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，受损的组织修复代表了不愈合的根本原因 伤口研究者团队最近的一系列研究发现了一种新的TRIM家族蛋白， MG 53是细胞膜修复机制的重要组成部分。在这里，我们提供的证据表明， MG 53是伤口愈合重要组分，重组人（rh）MG 53的局部应用 蛋白质具有促进慢性伤口愈合的潜力。MG 53能够使膜成核 修复角质形成细胞中的机制，从而保护表皮的损伤。MG 53存在于 细胞外溶液可以促进成纤维细胞响应于划痕创伤的迁移，从而有助于 伤口闭合的有效再上皮化。此外，我们还发现了一个新的发现，即循环MG 53与 上皮干细胞在伤口闭合的慢性和重塑阶段的参与。而 上皮干细胞不表达内源性MG 53蛋白，它们可以从循环中摄取MG 53， 对皮肤损伤的反应。rhMG 53的治疗功效将取决于制剂以及药物组合物。 提供MG 53的方法。将MG 53直接施用至伤口部位和通过免疫组织化学间接递送。 血管内注射是可能的方法，但由于MG 53在血管内的半衰期短，因此具有低功效。 血液循环重要的是，我们开发了一种适当的制剂，用于将rhMG 53持续递送至受试者。 以增强治疗效果。该项目的目标是测试MG 53 通过增强细胞膜修复和上皮干细胞功能促进慢性伤口愈合， rhMG 53的水凝胶制剂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MG 53在伤口愈合中的作用机制（目的1）; B）开发 基于水凝胶递送rhMG 53以治疗皮肤创伤（目标2）;和c）进行概念验证研究， rhMG 53/水凝胶用于慢性伤口愈合应用（目的3）。这些研究的完成应 我们对MG 53在伤口愈合中的生物学知识，并为MG 53的转化应用奠定基础。 rhMG 53治疗老年人慢性伤口的研究