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: 9892644
• 负责人: Song Hong
• 金额: $ 36.71万
• 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/9892644
• 关键词: 3xTg-AD mouse; Acids; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Award; Biodegradation; Brain; Brain Diseases; Cell model; Chronic; Clinical Trials; Dementia; Development; Diabetes Mellitus; Diabetic wound; Disease; Elderly; Enzyme Inhibitor Drugs; Enzymes; Fish Oils; Goals; Grant; Human; Hydroxyl Radical; Impaired wound healing; Impairment; Indigenous; Individual; Inflammation; Inflammatory; Kinetics; Knock-out; Metabolic Pathway; Mus; Natural regeneration; Neurons; Neurosciences; Oxidoreductase; Parents; Pathogenesis; Pathway interactions; Patients; Polyunsaturated Fatty Acids; Publishing; Reporting; Research; Research Personnel; Resolution; Role; Skin; Supplementation; Testing; Work; Wound Healing; aged; aging population; aqueous; chronic wound; diabetic wound healing; disorder control; effective therapy; experience; experimental study; inhibitor/antagonist; innovation; lipid mediator; multidisciplinary; neuronal survival; neuroprotectin D1; novel; novel therapeutics; prevent; repaired; trend; wound

ABSTRACT The parent active award for this application for NOT-AG-18-039 “Alzheimer's-focused administrative supplements” is to define the novel role and mechanisms of wound SPM biodegradation in the impairment of diabetic wound healing of the aged. Impeded resolution of chronic inflammation contributes substantially 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 the action of specialized pro-resolving lipid mediators (SPMs). Our prior research, including the active parent award, has identified a unique dysregulation, common to both Alzheimer's disease (AD) brains and diabetic wounds of the elderly, in the metabolic pathway leading to SPM biodegradation. Our long-term goal is to unravel mechanisms underlying the pathogenesis of both AD and chronic wounds and to develop effective therapies for these devastating diseases. Endogenous SPMs are biosynthesized enzymatically from essential polyunsaturated fatty acids. Two specific SPMs were identified in skin and brains: SPM1 (i.e., 14S,21R-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid) and neuroprotectin D1 (NPD1). Both SPM1 and NPD1 were diminished in brains of humans with AD or mouse AD models. We also identified the 15-hydroxyprostaglandin dehydrogenase (PGDH) degradation products of SPM1 and NPD1. We hypothesize that the exacerbated biodegradation of SPMs in brains contributes to AD pathogenesis. We will test this using mouse AD model, human neural cell models, PGDH inhibition and knockout, and our unique aqueous chiral (ac) LC-MS/MS lipidomics platform. The objective of this supplemental project is to initiate an exploration of the novel role and mechanisms of SPM biodegradation in AD pathogenesis. Aim 1. Test the prediction that the biodegradation deactivates the ability of endogenous SPM1 and NPD1 to protect against and ameliorate AD pathogenesis. 1A) Determine the kinetics of SPMs and their biodegradants in brains of mouse AD model and control using acLC-MS/MS. 1B) Assess the activities of biodegradants of SPM1 and NPD1 on specific AD pathogenesis using human neural cell models. Aim 2. Identify the key enzymatic pathway for SPM biodegradation in brains of mouse AD model and its role in AD pathogenesis. 2A) We will use inhibitors to decipher the roles of the enzyme for both SPM biodegradation and AD pathogenesis in mouse AD models. 2B) We will use mice with knockout of the key SPM degradation enzyme to verify the SPM biodegradation mechanism revealed by the enzyme inhibitors. Overall impact: This project will delineate the innovative SPM-biodegradation mechanism for AD pathogenesis. This mechanism is highly translational for the development of new therapeutics to prevent and ameliorate AD. The work proposed is within the scope of the active parent award that also aims to investigate SPM biodegradation as a mechanism for impaired repair and regeneration (but in active parent award, we focus on diabetic wounds of the aged), which meets the 3 criteria in NOT-AG-18-039 for this supplemental grant.

抽象的 家长对该申请的积极奖励为 NOT-AG-18-039“以阿尔茨海默氏症为重点的行政管理 补充剂”的目的是定义伤口SPM生物降解在损伤中的新作用和机制 老年人的糖尿病伤口愈合受阻对慢性炎症有很大影响。 衰老和糖尿病共同导致的愈合受损是解决慢性炎症的关键。 克服这种损害，可归因于专门的促溶解脂质介质的作用 （SPM）我们之前的研究，包括积极的家长奖，已经发现了一种独特的、常见的失调现象。 在导致阿尔茨海默病 (AD) 大脑和老年人糖尿病伤口的代谢途径中， 我们的长期目标是揭示 AD 发病机制。 和慢性伤口并开发针对这些破坏性疾病的有效疗法。 从必需的多不饱和脂肪酸中通过酶法生物合成了两种特定的 SPM。 皮肤和大脑：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) 在患有 AD 的人类或小鼠 AD 的大脑中均减少。 我们还鉴定了 15-羟基前列腺素脱氢酶 (PGDH) 降解产物。 我们发现大脑中 SPM 的生物降解加剧会导致 AD。 我们将使用小鼠 AD 模型、人类神经细胞模型、PGDH 抑制和抑制来测试这一点。 敲除，以及我们独特的水性手性 (ac) LC-MS/MS 脂质组学平台。 补充项目旨在探索 SPM 生物降解的新作用和机制 AD发病机制 目的 1.检验生物降解使内源性能力失活的预测。 SPM1 和 NPD1 可预防和改善 AD 发病机制 1A) 确定 SPM 和 NPD1 的动力学。 使用 acLC-MS/MS 评估小鼠 AD 模型和对照大脑中的生物降解物的活性。 使用人类神经细胞模型研究 SPM1 和 NPD1 的生物降解物对特定 AD 发病机制的影响。 确定小鼠 AD 模型大脑中 SPM 生物降解的关键酶途径及其在 AD 中的作用 2A) 我们将使用抑制剂来破译该酶在 SPM 生物降解和 小鼠 AD 模型中的 AD 发病机制 2B) 我们将使用关键 SPM 降解被敲除的小鼠。 酶来验证抑制剂酶揭示的 SPM 生物降解机制 总体影响：这。 项目将描述 AD 发病机制的创新 SPM 生物降解机制。 这项工作对于开发预防和改善 AD 的新疗法具有高度转化作用。 属于积极家长奖的范围，该奖项还旨在研究 SPM 生物降解作为 受损修复和再生机制（但在积极家长奖中，我们重点关注糖尿病伤口） 老年人），符合此补充补助金的 NOT-AG-18-039 中的 3 个标准。