SPM Biodegradation: A Novel Mechanism for Impaired Healing of Chronic Wounds in Aging

SPM 生物降解：一种治疗衰老过程中慢性伤口愈合受损的新机制

• 批准号: 9761418
• 负责人: Song Hong
• 金额: $ 18.38万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761418
• 关键词: Acids; Aging; Animals; Basic Science; Biodegradation; Biology; Caring; Chronic; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Diabetic ulcer; Diabetic wound; Elderly; Enzymes; Excision; Goals; Health; Human; Hydroxyl Radical; Impaired wound healing; Impairment; Inflammation; Injury; Knock-out; Knowledge; Modality; Mus; Outcome; Oxidoreductase; Pathway interactions; Pharmacology; Pilot Projects; Polyunsaturated Fatty Acids; Process; Resolution; Role; Skin wound; Splint Device; Testing; Therapeutic; Time; Ulcer; Wound Healing; aged; aqueous; chronic wound; clinically significant; db/db mouse; diabetic; diabetic wound healing; effective therapy; healing; improved; inhibitor/antagonist; lipid mediator; mouse model; neuroprotectin D1; novel; novel therapeutics; wound

ABSTRACT As stated in “PA-16-231 Non-healing Ulcerative Wounds in Aging (R21)”, “diabetic ulcers occur more commonly in the elderly... few studies have explored how aging impacts these (wound healing) processes and this gap in our understanding limits the applicability of novel therapies”. Impeded resolution of chronic inflammation contributes largely to the impairment of healing by the combination of aging and diabetes. Resolving chronic inflammation is pivotal in overcoming this impairment, and is attributable to specialized pro- resolving lipid mediators (SPMs). Our long-term goal is to delineate the mechanisms of healing impaired by diabetes and aging and develop better modalities for effective treatment of chronic wounds in the elderly. SPMs are endogenously made enzymatically from polyunsaturated fatty acids. SPMs in normally healing skin- wounds include SPM1 (i.e., 14S,21R-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid) and neuroprotectin D1 (NPD1). SPM1 and NPD1 can potently resolve chronic inflammation and restoring the healing of diabetic wounds. Chronic wounds of diabetic or aged humans and mice are SPM1 and NPD1 deficient and contain higher levels of SPM1 and NPD1 biodegradation products, compared to normally healing wounds, suggesting that the SPM deficiency is an important contributor to the healing impairment. Our pilot study found that SPM1 and NPD1 were converted to the degradation products by 15-hydroxyprostaglandin dehydrogenase (PGDH, the key endogenous enzyme that degrade hydroxyl-containing lipid mediators). Thus we hypothesize that the exacerbated biodegradation of wound SPMs is at least partially responsible for the healing impairment in diabetic wounds in the elderly. This will be tested in an established aged diabetic db/db mouse model of splinted excisional wounds. We will also use PGDH knockout and inhibition, and our unique aqueous chiral (ac) LC-UV-MS/MS lipidomics platform. Aim 1. Test the prediction that the biodegradation deactivates endogenous SPMs in healing the wounds of aged diabetic mice. 1A) Determine the time course of degradation of wound SPMs. We will establish the temporal profiles of biodegradants of wound SPMs of aged diabetic mice using acLC-UV-MS/MS. 1B) Test whether or not the SPM1 and NPD1 biodegradants are able to promote wound healing in mice. Aim 2. Test the prediction that suppressing the key enzymatic pathway for SPM biodegradation restores the wound healing in aged diabetic mice. We will determine the healing and inflammation resolution of wounds: 2A) of the aged diabetic mice with the key biodegradation enzyme PGDH blocked by inhibitors; and 2B) of mice with PGDH knocked out to verify the results from 2A. Overall impact: This project will define novel mechanisms and explore the therapeutic potential of suppressing the degradation of SPMs, in restoring the healing of diabetic wound in aging. These studies will fill the clinically significant gap of basic scientific knowledge about diabetic wounds in aging, lipid mediator biology, and pharmacology associated with SPMs. The proposed novel mechanism is highly translational.

抽象的 正如“PA-16-231 衰老过程中不愈合的溃疡性伤口 (R21)”中所述，“糖尿病性溃疡更容易发生” 通常在老年人中......很少有研究探讨衰老如何影响这些（伤口愈合）过程和 我们理解上的这种差距限制了新疗法的适用性”。 衰老和糖尿病的结合导致炎症在很大程度上损害了愈合。 解决慢性炎症是克服这种损害的关键，并且可归因于专门的亲 解决脂质介质（SPM）问题是我们的长期目标是阐明愈合受损的机制。 糖尿病和衰老的影响，并开发更好的方法来有效治疗老年人的慢性伤口。 SPM 是由正常愈合的皮肤中的多不饱和脂肪酸通过酶促生成的。 伤口包括SPM1（即14S,21R-二羟基-二十二碳五烯酸-4Z,7Z,10Z,12E,16Z,19Z-己烯酸）和 神经保护素 D1 (NPD1) 和 NPD1 可以有效解决慢性炎症并恢复神经功能。 糖尿病或老年人类和小鼠的慢性伤口的愈合是SPM1和NPD1。 与正常愈合相比，缺乏且含有较高水平的 SPM1 和 NPD1 生物降解产物 伤口，表明 SPM 缺陷是导致愈合障碍的重要因素。 研究发现SPM1和NPD1被15-羟基前列腺素转化为降解产物 脱氢酶（PGDH，降解含羟基脂质介质的关键内源酶）。 我们认为，伤口 SPM 的生物降解加剧至少是造成这种情况的部分原因。 老年人糖尿病伤口愈合障碍 这将在已建立的老年糖尿病数据库/数据库中进行测试。 我们还将使用 PGDH 敲除和抑制，以及我们独特的夹板切除伤口小鼠模型。 水性手性 (ac) LC-UV-MS/MS 脂质组学平台 目标 1. 测试生物降解的预测。 使内源性 SPM 在老年糖尿病小鼠伤口愈合过程中失活 1A) 确定治疗的时间进程。 我们将建立老年人伤口 SPM 生物降解物的时间分布。 使用 acLC-UV-MS/MS 的糖尿病小鼠 1B) 测试 SPM1 和 NPD1 生物降解剂是否能够 目标 2. 测试抑制关键酶途径的预测。 SPM 生物降解可恢复老年糖尿病小鼠的伤口愈合。我们将确定愈合和愈合情况。 伤口炎症消退：2A) 使用关键生物降解酶 PGDH 治疗老年糖尿病小鼠 被抑制剂阻断；和 2B) 敲除 PGDH 的小鼠，以验证 2A 的结果： 该项目将定义新的机制并探索抑制降解的治疗潜力 SPM 在恢复衰老过程中糖尿病伤口的愈合方面的研究将填补临床上的重大空白。 有关衰老、脂质介质生物学和药理学糖尿病伤口的基础科学知识 所提出的新机制具有高度的转化性。