A role for peripheral NAAA-regulated lipid signaling in the control of hyperalgesic priming

外周 NAAA 调节的脂质信号在痛觉过敏启动控制中的作用

• 批准号: 10784207
• 负责人: Yannick Fotio
• 金额: $ 23.83万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784207
• 关键词: Lipids; NAAA gene; Peripheral; Role; Signal Transduction

Chronic pain is an enormous global health challenge that affects ~50 million adults in the United States alone. Developing safe and effective treatments for this condition is thus of critical importance and requires a deeper understanding of the molecular and cellular mechanisms that lead to pain chronification. It is my career goal to make meaningful contributions toward the solution of this challenging problem. My previous research demonstrated that the transition from acute to chronic pain after paw injury requires a transient suppression of palmitoylethanolamide (PEA) signaling at PPAR-α (peroxisome proliferator-activated receptor-α) in the spinal cord. This event redirects local spinal cord metabolism from mitochondrial respiration toward aerobic glycolysis. This metabolic reprograming (i) generates biomass needed to support synaptic plasticity and (ii) precipitates an energy crisis that contributes to pain chronification. In this K99/R00 application, I propose to test the novel hypothesis that the enzyme N-Acylethanolamine Acid Amidase (NAAA), which deactivates PEA, plays a pivotal role in the emergence of hyperalgesic priming (HP), a model used to study the susceptibility to chronic pain after acute insults. This idea is supported by my recent study indicating that NAAA is expressed at high levels in cell lineages that mediate pain perception and immune reactions and its activity is enhanced by priming stimuli or tissue damage. In addition, NAAA ablation forestall the emergence of HP through a mechanism that requires, at least in part, the restoration of cellular energy balance. These results led the central hypothesis that increased NAAA activity following acute injury might promote the emergence of HP by suppressing intracellular PEA signaling, which is associated with a metabolic shift from respiration, toward aerobic glycolysis. This research program has three pertinent aims to test this hypothesis. In Aim 1, I will utilize a combination of genetic and pharmacological tools to identify the receptor systems involved in NAAA-mediated HP. I hypothesize that NAAA acts by dampening PPAR-α signaling, though other receptors could be involved. In Aim 2, I will identify peripheral cell types involved in NAAA-mediated HP, by answering two questions: (i) does Naaa loss-of-function/gain-of-function in the dorsal root ganglia (DRG) affects the development of HP? and (ii) does priming agents increase NAAA expression in the DRG? Aim 3 will elucidate the molecular mechanism through which NAAA induces HP. I will use transcriptomic, biochemical and pharmacological strategies to probe the role of mitochondrial respiration in NAAA-mediated HP. Collectively, the application will investigate a highly novel and previously unrecognized role of NAAA in HP. The proposal is significant because it addresses an unmet public health need. If successful, it will open new avenues to develop transformative therapies that will be effective in individuals at risk of chronic pain.

慢性疼痛是一个巨大的全球健康挑战，仅在美国就影响到约5000万成年人。 因此，为这种疾病开发安全有效的治疗方法至关重要，需要更深入的研究。 了解导致疼痛慢性化的分子和细胞机制。这是我的职业目标 为解决这一具有挑战性的问题做出有意义的贡献。我之前的研究 表明，从急性过渡到慢性疼痛后，爪子受伤需要一个短暂的抑制 棕榈酰乙醇胺（PEA）信号在过氧化物酶体增殖物激活受体-α（过氧化物酶体增殖物激活受体-α）在 脊髓这一事件将局部脊髓代谢从线粒体呼吸转向有氧呼吸 糖酵解这种代谢重编程（i）产生支持突触可塑性所需的生物量，以及（ii） 加速了一场能量危机，导致了疼痛的慢性化。 在这个K99/R 00应用程序中，我建议测试新的假设，即酶N-酰基乙醇胺酸 酰胺酶（NAAA），使PEA失活，在痛觉过敏启动（HP）的出现中起关键作用， 用于研究急性损伤后对慢性疼痛的易感性的模型。这个想法得到了我的支持。 最近的一项研究表明，NAAA在介导疼痛感知的细胞谱系中以高水平表达 和免疫反应，并且其活性通过引发刺激或组织损伤而增强。此外，NAAA 消融通过一种机制来阻止HP的出现，该机制至少部分地需要恢复 细胞能量平衡这些结果导致了核心假设，即急性脑梗死后NAAA活性增加， 损伤可能通过抑制细胞内PEA信号而促进HP的出现， 代谢从呼吸转变为有氧糖酵解。 本研究计划有三个相关的目标来验证这一假设。在目标1中，我将使用一个组合 遗传和药理学工具，以确定参与NAAA介导的HP受体系统。我 假设NAAA通过抑制PPAR-α信号传导起作用，尽管其他受体也可能参与其中。在 目的2，我将通过回答两个问题来确定参与NAA介导的HP的外周细胞类型：（i） 背根神经节（DRG）中的Naaa功能丧失/功能获得是否影响HP的发展？ 和（ii）引发剂是否增加DRG中NAAA的表达？目标3将阐明分子 NAAA诱导HP的机制。我会用转录组学，生物化学和药理学 策略，以探测线粒体呼吸的作用，在NAA介导的HP。 总的来说，该应用程序将研究NAAA在HP中的高度新颖且先前未被认识的作用。 该提案意义重大，因为它解决了尚未满足的公共卫生需求。如果成功，它将开辟新的 开发变革性疗法的途径，这些疗法对有慢性疼痛风险的个体有效。