A Novel Resolution Strategy for Chronic Inflammation and Impaired Healing of Wounds in Aging

一种针对衰老过程中慢性炎症和伤口愈合受损的新解决策略

• 批准号: 9885278
• 负责人: Song Hong
• 金额: $ 31.35万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885278
• 关键词: Aging; Amides; Amino Acids; Amputation; Arginine; Attenuated; Biocompatible Materials; Blood Vessels; Chronic; Clinical; Data; Docosahexaenoic Acids; Drug Delivery Systems; Elderly; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Esters; Fibroblasts; Generations; Goals; Growth; Growth Factor; Hour; Impaired healing; Impaired wound healing; Impairment; Inflammation; Inflammatory; Interleukin-10; Kinetics; Knowledge; Lead; Mus; Natural regeneration; Omega-3 Fatty Acids; Phase; Phenotype; Play; Process; Production; Property; Proteins; Publishing; Regimen; Resolution; Role; Signal Transduction; Skin; TNF gene; Testing; Therapeutic; Time; Topical application; Vascular Endothelial Growth Factors; age related; aged; aging population; base; biomaterial compatibility; cell motility; chronic ulcer; cytokine; diabetic wound healing; effective therapy; healing; improved; in vitro testing; injury and repair; innovation; lipid mediator; macrophage; migration; multidisciplinary; non-healing wounds; novel; platelet-derived growth factor BB; prevent; regenerative; response; restoration; skin ulcer; stem cells; therapy development; translational approach; wound; wound care; wound closure; wound healing

ABSTRACT Age-related chronic inflammation is a key factor that prevents wound healing, but no effective therapy currently exists to cure non-healing wounds in the aging population. This R21 project, submitted in response to “PA-16- 231 Non-healing Ulcerative Wounds in Aging,” will explore a novel translational strategy for resolving chronic inflammation and restoring healing of non-healing ulcers in aging. Resolution of chronic inflammation is critical for restoration of healing process and appears to require the action of maresin-like lipid mediators (MarLs), which are produced by macrophages (Ms), resolve inflammation, and promote wound healing. Our long- term goal is to overcome the impairment of wound healing in aging. Toward this goal, we discovered that two endogenous wound MarLs (MarL1 and MarL3, derived from ω-3 docosahexaenoic acid) reverse this impairment. Our published data showed that MarL3 enhances diabetic wound healing and promotes the expression of reparative VEGF, PDGF-BB, and IL10, and the switch to reparative Ms and that it is likely to act via PI3K signaling. MarL3 also promotes wound blood-vessel growth and VEGF formation by endothelial cells. By contrast, MarL1 promotes the production of regenerative growth factor HGF and attenuates M production of pro-inflammatory TNFα. MarL1 also enhances M promoted migration of epithelial cells, fibroblasts, and stem cells. Application of MarL1 to wounds of aged mice improves healing. However, the therapeutic potential of MarLs is limited, because topically applied MarLs are eliminated from wounds within a few hours, whereas wound healing takes many days. Wound healing also involves multiple processes across this long time course, and many of these steps could be promoted by MarLs. In preliminary studies, we obtained sustained release of MarL1 to wounds using MarL1 embedded in amino acid (arginine)-based poly(ester amide) protein-mimic (AA-PEA) microparticles (µPs). AA-PEAs are a new generation of biomaterials that are biocompatible, biodegradable, and non-toxic. The MarL1 embedded in AA-PEA-µPs was more effective than MarL1 alone in promoting wound closure in aging. Our hypothesis is that a sustained release of MarLs to wounds will resolve inflammation and overcome the aging-impairment of healing. Our objective is to develop and assess the ability of our innovative µP-sustained release of MarLs to restore wound healing in the aged. Specific Aim 1. A) Develop the MarL-loaded µPs to control and sustain MarL- release to wounds of aged mice and determine kinetics of MarL release in wounds. B) Determine the optimal sustained MarL release from µPs and administration regimens for resolving inflammation and restoring healing (re-epithelialization, blood vessel regeneration, skin breaking-strength) of aged mice. This project will use µPs- sustained-release MarLs to identify an innovative strategy as well as therapeutic leads to overcome the impairment of healing in non-healing wounds of the elderly. It will also provide a new knowledge about the temporal relationship between the resolution of inflammation and healing of wounds in aging.

抽象的 与年龄有关的慢性炎症是阻止伤口愈合的关键因素，但目前尚无有效的治疗 存在于治愈衰老人群中的非治疗伤口。该R21项目是根据“ PA-16-- 231衰老中的非治疗溃疡伤口，”将探索一种解决慢性的新型翻译策略 衰老中非愈合溃疡的炎症和恢复。慢性感染的分辨率至关重要 为了恢复愈合过程，似乎需要采取类似母体的脂质介质（MARLS）的作用， 由巨噬细胞（MS）产生的，解决注射并促进伤口愈合。我们的长期 术语目标是克服衰老中伤口愈合的损害。达到这个目标，我们发现两个 内源性伤口泥浆（MARL1和MARL3，源自ω-3 docosahexaenoic Acid）逆转了这一点 损害。我们发布的数据表明，MARL3增强了糖尿病伤口的愈合并促进 调整VEGF，PDGF-BB和IL10的表达以及转向率的MS的转换很可能 通过PI3K信号传导行动。 MARL3还促进了内皮的伤口血管生长和VEGF形成 细胞。相比之下，MARL1促进了再生生长因子HGF的产生，并减轻了M 促炎性TNFα的产生。 MARL1还增强了M促进上皮细胞的迁移， 成纤维细胞和干细胞。 MARL1在老年小鼠伤口中的应用可改善愈合。但是， Marls的治疗潜力受到限制，因为局部施用的Marl被从A内的伤口中消除 几个小时，而伤口愈合需要很多天。伤口愈合还涉及多个过程 这段长期课程以及许多这些步骤都可以由Marls提升。在初步研究中，我们 使用嵌入氨基酸（精氨酸）的MARL1持续释放MARL1向伤口释放到伤口 聚（酯酰胺）蛋白质模拟（AA-PEA）微粒（µPS）。 AA-PEAS是新一代 生物相容性，可生物降解且无毒的生物材料。嵌入在AA-PEA-µPS中的MARL1为 比单独促进衰老的伤口闭合比MARL1更有效。我们的假设是一个持续的 释放到伤口将释放将解决感染并克服愈合愈合的损害。我们的 目的是开发和评估我们创新的MARL释放恢复的能力 年龄的伤口愈合。特定目的1。a）开发加载的Marl µPS来控制和维持MARL- 释放为年龄小鼠的胜利，并确定伤口中MARL释放的动力学。 b）确定最佳 从µPS和管理方案中持续释放MAL，以解决注射和恢复愈合 （重新上皮，血管再生，皮肤破裂 - 强度），年龄小鼠。该项目将使用µps- 持续释放的马尔斯识别创新策略以及治疗性导致克服 较早的非愈合伤口中治愈的损害。它还将提供有关 炎症的解决与衰老中奖金的治愈之间的暂时关系。