FABPs: Novel Roles in Pain and Inflammation

描述（由申请人提供）：慢性疼痛每年造成数十亿美元的生产力损失和医疗费用。目前的治疗策略在整个人群中存在部分疗效，导致疼痛缓解不足。此外，许多长期施用的镇痛剂（例如，吗啡或奥施康定），虽然实际上有效，但会导致耐受和成瘾。因此，确定新的药物靶点以开发非成瘾性镇痛药势在必行。生物活性脂质如内源性大麻素和N-酰基乙醇胺（NAE）调节整个神经系统的伤害感受。临床前研究表明，调节内源性大麻素和NAE catalysts代表了一种有吸引力的治疗疼痛的策略，也没有精神作用。最近，我们确定了脂肪酸结合蛋白（FABPs）作为第一个细胞内载体， 内源性大麻素和NAE的转运和失活。迄今为止，尚不清楚FABP是否在体内调节内源性大麻素和NAE张力。 该项目的中心目标是确定FABPs是否在体内调节内源性大麻素和NAE信号传导和失活，并确定抑制FABPs是否产生内源性大麻素和NAE介导的抗伤害感受。我们将通过首先确定消融FABP是否减少炎性疼痛模型中的伤害感受来实现这一点。然后，我们将确定FABP亚型，调节疼痛和炎症，通过互补的方法相结合：药理学操作和转基因FABP敲除小鼠缺乏特定的FABP子集。在本提案的第二个目标中，我们将采用基于质谱的脂质组学来确定FABP是否在相关解剖部位调节体内内源性大麻素和NAE水平，从而确定FABP抑制是否产生内源性大麻素和NAE介导的镇痛作用。最后，在最后一个目标中，我们将检查伴随FABP抑制的外周细胞因子和前列腺素水平的变化，并确定FABP抑制是否改变伤害性神经元的敏化。总之，本研究将确定FABP作为调节伤害感受和炎症的新型蛋白质，并将评估个体FABP在体内内源性大麻素和NAE失活中的作用。通过将新的作用归因于FABP在伤害感受中，这项工作将为未来FABP靶向治疗的发展提供基础，从而可能导致改善镇痛剂。

DESCRIPTION (provided by applicant): Chronic pain accounts for billions of dollars of lost productivity and medical expenses annually. Current treatment strategies suffer from partial efficacy across the population, resulting in inadequate pain relief. Furthermore, many chronically administered analgesics (e.g., morphine or oxycontin), while actually effective, lead to tolerance and addiction. Consequently, it is imperative to identify novel drug targets for the development of non-addictive analgesics. Bioactive lipids such as endocannabinoids and N-acylethanolamines (NAEs) regulate nociception throughout the nervous system. Preclinical studies suggest that modulation of endocannabinoid and NAE catabolism represents an attractive strategy for the treatment of pain that is also devoid of psychotropic effects. Recently we identified fatty acid binding proteins (FABPs) as the first intracellular carriers that regulate endocannabinoid and NAE transport and inactivation in vitro. To date, it is not known whether FABPs regulate the endocannabinoid and NAE tone in vivo. The central goals of this project are to determine whether FABPs regulate endocannabinoid and NAE signaling and inactivation in vivo and to ascertain whether inhibition of FABPs produces endocannabinoid- and NAE-mediated antinociception. We will accomplish this by first determining whether ablation of FABPs reduces nociception in models of inflammatory pain. We will then identify the FABP subtypes that modulate pain and inflammation through a combination of complementary approaches: pharmacological manipulation and transgenic FABP knockout mice lacking specific subsets of FABPs. In the second aim of this proposal, we will employ mass spectrometry-based lipidomics to determine whether FABPs regulate endocannabinoid and NAE levels in vivo at relevant anatomical sites and consequently whether FABP inhibition produces endocannabinoid- and NAE-mediated analgesia. Finally, in the last aim, we will examine changes in peripheral cytokine and prostaglandin levels that accompany FABP inhibition and determine whether FABP inhibition alters the sensitization of nociceptive neurons. In summary, this study will identify FABPs as novel proteins that regulate nociception and inflammation and will evaluate the roles for individual FABPs in endocannabinoid and NAE inactivation in vivo. By ascribing novel roles to FABPs in nociception, this work will provide a foundation for the development of future FABP targeting therapeutics that may lead to improved analgesics.