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

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，为这种情况开发安全有效的治疗方法至关重要，并需要更深层次的 了解导致疼痛时代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作出有意义的贡献。我之前的研究 证明了脚掌损伤后从急性疼痛到慢性疼痛的过渡需要短暂的抑制。 棕榈酰乙醇胺在PPAR-α(过氧化体增殖物激活受体-α)信号转导中的作用 脊髓。这一事件将局部脊髓代谢从线粒体呼吸重定向为有氧代谢。 糖酵解。这种代谢再编程(I)产生支持突触可塑性所需的生物量，以及(Ii) 导致能量危机，从而导致疼痛时代化。 在K99/R00的应用中，我建议测试新的假设，即N-乙酰乙醇胺酸酶 酰胺酶(NAAA)使PEA失活，在痛觉过敏启动(HP)的产生中起着关键作用。 一种用于研究急性侮辱后慢性疼痛易感性的模型。这个想法得到了我的支持 最近的研究表明，NAAA在介导痛觉的细胞系中高水平表达 免疫反应及其活性可通过激发刺激或组织损伤而增强。此外，NAAA 消融通过一种机制阻止幽门螺杆菌的出现，这种机制至少需要部分恢复 细胞能量平衡。这些结果导致了一个中心假设，即急性胰腺炎后NAAA活性增加 损伤可能通过抑制细胞内的PEA信号促进幽门螺杆菌的出现，这与 代谢从呼吸转向有氧糖酵解。 这项研究计划有三个相关的目的来检验这一假设。在目标1中，我将使用一个组合 遗传和药理学工具来识别NAAA介导的幽门螺杆菌所涉及的受体系统。我 假设NAAA通过抑制PPAR-α信号发挥作用，尽管其他受体可能参与其中。在……里面 目的2，我将通过回答两个问题来确定NAAA介导的幽门螺杆菌涉及的外周细胞类型：(I) 背根神经节(DRG)的NAAA功能丧失/功能获得是否影响HP的发展？ 以及(Ii)启动剂是否增加了背根节NAAA的表达？目标3将阐明分子 NAAA诱导幽门螺杆菌的机制。我会用转录，生化和药理学 探讨线粒体呼吸在NAAA介导的幽门螺杆菌中的作用。 总而言之，这项申请将调查NAAA在惠普中一个非常新颖、以前没有被认识到的角色。 这项提案意义重大，因为它解决了一个未得到满足的公共卫生需求。如果成功，它将打开新的 开发对有慢性疼痛风险的个人有效的变革性疗法的途径。

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.