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 年龄相关的慢性炎症是阻碍伤口愈合的关键因素，但目前尚无有效治疗方法 该 R21 项目是为了响应“PA-16-”而提交的。 231 衰老过程中不可愈合的溃疡性伤口”将探索一种解决慢性溃疡的新转化策略 炎症和恢复衰老中不愈合溃疡的愈合对于慢性炎症的解决至关重要。 为了恢复愈合过程，似乎需要 maresin 样脂质介质 (MarLs) 的作用， 由巨噬细胞 (Ms) 产生，可解决炎症并促进伤口愈合。 长期目标是克服衰老过程中伤口愈合的障碍。为了实现这一目标，我们发现了两个目标。 内源性伤口MarLs（MarL1和MarL3，源自ω-3二十二碳六烯酸）逆转了这一点 我们发表的数据表明，MarL3 可增强糖尿病伤口愈合并促进糖尿病伤口愈合。 修复性 VEGF、PDGF-BB 和 IL10 的表达，以及向修复性 Ms 的转换，并且很可能 MarL3 还通过 PI3K 信号传导发挥作用，促进伤口血管生长和内皮细胞 VEGF 的形成。 相比之下，MarL1 促进再生生长因子 HGF 的产生并减弱 M。 MarL1 的产生还增强 M 促进上皮细胞的迁移， 然而，将 MarL1 应用于老年小鼠的伤口可以改善愈合。 MarLs 的治疗潜力有限，因为局部使用的 MarLs 会在一定时间内从伤口中消除。 伤口愈合需要数小时，而伤口愈合还涉及多个过程。 这是一个漫长的过程，在初步研究中，我们可以推动其中许多步骤。 使用嵌入氨基酸（精氨酸）的 MarL1 获得了 MarL1 向伤口的持续释放 聚（酯酰胺）蛋白模拟物 (AA-PEA) 微粒 (μP) 是新一代的。 嵌入 AA-PEA-μP 中的 MarL1 具有生物相容性、可生物降解性和无毒性。 在促进衰老伤口闭合方面比单独使用 MarL1 更有效。 向伤口释放 MarL 将解决炎症并克服衰老对愈合的损害。 目标是开发和评估我们创新的 µP 持续释放 MarL 恢复的能力 具体目标 1. A) 开发负载 MarL 的 µP 以控制和维持 MarL- 释放到老年小鼠的伤口并确定 MarL 在伤口中的释放动力学 B) 确定最佳值。 µP 中持续释放 MarL 和用于解决炎症和恢复愈合的给药方案 （上皮再生、血管再生、皮肤断裂强度）该项目将使用 µPs-。 缓释MarLs以确定创新策略以及治疗线索来克服 它还将提供有关老年人不愈合伤口愈合障碍的新知识。 衰老过程中炎症消退和伤口愈合之间的时间关系。