SPM BIODEGRADATION: A NOVEL MECHANISM FOR IMPAIRED HEALING OF CHRONIC WOUNDS IN AGING

摘要 父母主动奖为这一申请NOT-AG-18 - 039 "阿尔茨海默氏症为重点的行政 补充剂"是为了定义创伤SPM生物降解在损伤中的新作用和机制， 老年糖尿病创面愈合。慢性炎症的消退受阻在很大程度上导致了 由于衰老和糖尿病的结合而损害愈合。解决慢性炎症是关键， 克服这种损害，并归因于专门的促分解脂质介质的作用 （SPM）。我们之前的研究，包括积极的父母奖，已经确定了一个独特的失调，常见的 阿尔茨海默病（AD）的大脑和糖尿病伤口的老年人，在代谢途径导致 到SPM生物降解。我们的长期目标是阐明AD和AD的发病机制， 和慢性伤口，并为这些毁灭性的疾病开发有效的治疗方法。内源性SPM是 从必需的多不饱和脂肪酸酶促生物合成。两个特定的SPM被确定， 皮肤和脑：SPM 1（即，14S，21R-二羟基-二十二碳-4Z，7Z，10Z，12E，16Z，19Z-六烯酸）和 神经保护素D1（NPD 1）。SPM 1和NPD 1在患有AD的人或小鼠的脑中均减少 模型我们还确定了15-羟基前列腺素脱氢酶（PGDH）的降解产物， SPM 1和NPD 1。我们推测，大脑中SPM的生物降解加剧有助于AD 发病机制我们将使用小鼠AD模型、人神经细胞模型、PGDH抑制和 我们独特的水性手性（ac）LC-MS/MS脂质组学平台。的目的 补充项目是开始探索SPM生物降解的新作用和机制， AD发病机制目标1.验证了生物降解对内源性微生物降解能力的预测 SPM1和NPD1对预防和改善AD发病机制的作用。1A）确定SPM的动力学，以及 使用acLC-MS/MS在小鼠AD模型和对照的脑中评估它们的生物降解物。 使用人神经细胞模型，研究SPM 1和NPD 1生物降解物对特定AD发病机制的影响。目标2. SPM在AD小鼠脑内降解的关键酶途径及其在AD发病中的作用 发病机制2A）我们将使用抑制剂来解释酶在SPM生物降解和 小鼠AD模型中的AD发病机制。2B）我们将使用敲除关键SPM降解的小鼠 以验证酶抑制剂揭示的SPM生物降解机理。总体影响： 项目将描述AD发病机制的创新SPM生物降解机制。这个机制是 对于开发预防和改善AD的新疗法具有高度转化性。工作提出的 是在积极的父母奖的范围内，也旨在调查SPM生物降解作为一种 受损修复和再生的机制（但在积极的父母奖，我们专注于糖尿病伤口， 老年人），符合NOT-AG-18 - 039中关于该补充补助金的3项标准。

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.