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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）：慢性疼痛每年造成数十亿美元的生产力损失和医疗费用。目前的治疗策略在人群中效果有限，导致疼痛缓解不足。此外，许多长期服用的镇痛药（例如吗啡或奥施康定）虽然实际上有效，但会导致耐受性和成瘾性。因此，必须确定新的药物靶点来开发非成瘾性镇痛药。内源性大麻素和 N-酰基乙醇胺 (NAE) 等生物活性脂质可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 分解代谢是治疗疼痛的一种有吸引力的策略，但也没有精神作用。最近，我们发现脂肪酸结合蛋白（FABP）是第一个调节细胞内的载体。内源性大麻素和 NAE 的体外转运和失活。迄今为止，尚不清楚 FABP 是否在体内调节内源性大麻素和 NAE 音调。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 信号传导和失活，并确定 FABP 的抑制是否会产生内源性大麻素和 NAE 介导的镇痛作用。我们将通过首先确定 FABP 的消融是否减少炎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的组合来识别调节疼痛和炎症的 FABP 亚型：药理学操作和缺乏 FABP 特定子集的转基因 FABP 敲除小鼠。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 是否在体内调节相关解剖部位的内源性大麻素和 NAE 水平，从而确定 FABP 抑制是否会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感性。总之，本研究将鉴定 FABP 作为调节伤害感受和炎症的新型蛋白质，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 在伤害感受中的新作用，这项工作将为未来 FABP 靶向疗法的开发奠定基础，从而可能改善镇痛药。