FABPs: Novel Roles in Pain and Inflammation

FABP：在疼痛和炎症中的新作用

基本信息

批准号：
8874187
负责人：
Martin Kaczocha
金额：
$ 34.8万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874187
关键词：
2-arachidonylglycerol Ablation Absence of pain sensation Accounting Acute inflammatory pain Adverse effects Afferent Neurons Analgesics Anti-Inflammatory Agents Anti-inflammatory Behavior Brain Catabolism Cell membrane Cultured Cells Dependency Development Drug Targeting Endocannabinoids Enzymes Foundations Future Genetic Goals Health In Vitro Individual Inflammation Inflammation Mediators Inflammatory Knockout Mice Knowledge Lead Lipids Mass Spectrum Analysis Measures Mediating Medical Modeling Morphine Mus Mutant Strains Mice Nervous system structure Neurons Nociception Nociceptors Output Oxycodone PPAR alpha Pain Peripheral Peripheral Nerves Population Productivity Prostaglandin Production Prostaglandins Protein Inhibition Proteins Risk Role Signal Transduction Site Spinal Cord Testing Time Tissues Transgenic Organisms Wild Type Mouse Work addiction anandamide base cannabinoid receptor chronic pain cytokine drug development fatty acid amide hydrolase fatty acid-binding proteins improved in vivo inflammatory pain inhibitor/antagonist novel oleoylethanolamide palmidrol preclinical study receptor therapeutic target treatment strategy

项目摘要

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.

描述（由申请人提供）：每年的慢性疼痛占数十亿美元的生产力和医疗费用的损失。当前的治疗策略在整个人群中都有部分疗效，导致疼痛缓解不足。此外，许多长期施用的镇痛药（例如吗啡或奥昔康）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标，以开发非成瘾性镇痛药。生物活性脂质（例如内源性大麻素和N-酰基乙醇胺（NAES））调节整个神经系统的伤害受伤。临床前研究表明，内源性大麻素和NAE分解代谢的调节代表了治疗疼痛的有吸引力的策略，也没有精神作用。最近，我们确定脂肪酸结合蛋白（FABPS）是调节的第一个细胞内载体内源性大麻素和NAE转运和体外失活。迄今为止，尚不清楚Fabps在体内是否调节内源性大麻素和NAE张力。该项目的核心目标是确定FABPS在体内调节内源性大麻素和NAE信号传导以及失活以及确定FABPS的抑制是否会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FabPS的消融是否会减少炎症性疼痛模型中的伤害感受来实现这一目标。然后，我们将通过互补方法组合来确定调节疼痛和炎症的FABP亚型：药理操纵和缺乏特定FABPs子集的药理学操纵和转基因FABP敲除小鼠。在该提案的第二个目的中，我们将采用质谱基脂肪组学来确定FABPS在相关的解剖部位的体内调节内源性大麻素和NAE水平是否在体内调节，因此FABP抑制是否会产生内源性大麻素和NAE-NAE介导的分析。最后，在最后一个目标中，我们将检查伴随FABP抑制的周围细胞因子和前列腺素水平的变化，并确定FABP抑制是否会改变伤害性神经元的敏感性。总而言之，这项研究将确定FABP是调节伤害感和炎症的新型蛋白质，并将评估单个Fabps在体内内源性大麻素和NAE失活中的作用。通过将新颖的角色归因于伤害感受，这项工作将为未来的FABP靶向治疗剂的发展提供基础，从而可能导致改善的镇痛药。