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 该申请的父母主动奖 补充剂”是为了定义伤口SPM生物降解的新作用和机制 老年人的糖尿病伤口愈合。慢性感染的阻碍分辨率对 衰老和糖尿病的结合损害治愈。解决慢性炎症至关重要 克服这种障碍，这归因于专业促进脂质介质的作用 （spms）。我们先前的研究，包括活跃的父母奖，已经确定了独特的失调，常见 在代谢途径中，阿尔茨海默氏病（AD）大脑和糖尿病伤口 到SPM生物降解。我们的长期目标是阐明两者的发病机理的基础机制 和慢性伤口，并为这些毁灭性疾病开发有效的疗法。内源性SPM是 生物合成从必需的多不饱和脂肪酸中酶促的。在 皮肤和大脑：SPM1（即14s，21r-二羟基docosa-4z，7z，10z，10z，12e，16z，19z-hexaenoic） 神经保护素D1（NPD1）。 SPM1和NPD1都在AD或小鼠AD的人的大脑中减少 型号。我们还确定了15-羟基丙烷蛋白脱氢酶（PGDH）的降解产物 SPM1和NPD1。我们假设大脑中SPMS的加剧生物降解有助于AD 发病。我们将使用小鼠AD模型，人类神经元细胞模型，PGDH抑制和 淘汰赛，以及我们独特的手性水（AC）LC-MS/MS脂质组学平台。这个目的 补充项目是启动对SPM生物降解的新作用和机制的探索 AD发病机理。目标1。测试生物降解停用内源能力的预测 SPM1和NPD1可预防和改善AD发病机理。 1A）确定SPM和 它们在小鼠AD模型的大脑中的生物降解剂，并使用ACLC-MS/MS对照。 1b）评估活动 SPM1和NPD1的生物降解物使用人神经细胞模型在特定的AD发病机理上。目标2。 确定小鼠AD模型大脑中SPM生物降解的关键酶促途径及其在AD中的作用 发病。 2a）我们将使用抑制剂来破译SPM生物降解和 小鼠广告模型中的AD发病机理。 2b）我们将使用小鼠与密钥SPM降解的敲除 酶以验证酶抑制剂揭示的SPM生物降解机制。总体影响：这 项目将描述AD发病机理的创新SPM-BiDEDRADADITATION机制。这种机制是 高度翻译为开发新的治疗剂，以预防和改善AD。提出的工作 在主动父母奖的范围内，该奖项还旨在调查SPM生物降解作为一个 维修和再生受损机制（但在主动父母奖励中，我们专注于糖尿病伤口 年龄），符合这项补充赠款中NOT-AG-18-039中的3个标准。