FABPs: Novel Roles in Pain and Inflammation

描述(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，许多长期使用的止痛药(如吗啡或奥施康定)，虽然实际上有效，但会导致耐受性和成瘾。因此，必须确定新的药物靶点，以开发非成瘾性止痛药。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性感受。临床前研究表明，调节内源性大麻素和NAE分解代谢是治疗也没有精神药物作用的疼痛的一种有吸引力的策略。最近，我们发现脂肪酸结合蛋白(FABP)是第一个在细胞内调节 内源性大麻素和NAE在体外的转运和失活。到目前为止，FABP是否调节体内的内源性大麻素和NAE音调尚不清楚。该项目的中心目标是确定FABP是否在体内调节内源性大麻素和NAE信号和失活，并确定FABPs的抑制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性感觉来实现这一点。然后，我们将通过互补的方法组合来确定调节疼痛和炎症的FABP亚型：药物操作和缺乏特定FABP亚群的转基因FABP基因敲除小鼠。在这项提议的第二个目的中，我们将使用基于质谱学的脂质组学来确定FABP是否调节体内相关解剖部位的内源性大麻素和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。最后，在最后一个目标中，我们将检测伴随FABP抑制的外周细胞因子和前列腺素水平的变化，并确定FABP抑制是否改变了伤害性神经元的敏感性。综上所述，这项研究将确定FABP是调节伤害性感觉和炎症的新蛋白，并将评估单个FABP在体内内源性大麻素和NAE失活中的作用。通过赋予FABP在伤害性感受中的新作用，这项工作将为未来FABP靶向疗法的发展提供基础，从而可能导致改进的止痛药。

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.