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：
10403597
负责人：
Martin Kaczocha
金额：
$ 39.55万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403597
关键词：
Ablation Absence of pain sensation Adult Affect Afferent Neurons Agonist Analgesics Anti Inflammatory Analgesics Attenuated Biochemical Biological Assay Brain CNR1 gene Calcium Cannabinoids Cells Chronic Coupled Data Development Economic Burden Endocannabinoids Enzymes Foundations Genetic Goals Histologic Human Hyperalgesia Image In Vitro Inflammation Inflammation Mediators Inflammatory Ion Channel Knowledge Lead Lipids Mediating Metabolism Molecular Mus Nerve Growth Factors Nociceptors Non-Steroidal Anti-Inflammatory Agents Opiate Addiction Opioid Outcome Outcome Study Output PPAR alpha Pain Pathway interactions Peripheral Pharmacology Phosphotransferases Population Positioning Attribute Process Protein Inhibition Regulation Role Signal Transduction Spinal Cord Spinal Ganglia Stimulus Testing Thermal Hyperalgesias Tissues Treatment Factor Up-Regulation Work addiction addiction liability anandamide antagonist cannabinoid receptor cell type chronic pain chronic pain management experimental study fatty acid-binding proteins in vivo inflammatory pain insight lipidomics macrophage new therapeutic target novel opioid use p38 Mitogen Activated Protein Kinase pain reduction pain relief pain sensitivity palmidrol prescription opioid abuse receptor release factor vanilloid receptor subtype 1

项目摘要

Chronic pain affects one third of the adult population and presents a massive societal and economic burden. Current treatment approaches typically include non-steroidal anti-inflammatory drugs that suffer from limited efficacy and opioids, which possess significant addiction liability. Consequently, there is an urgent need to identify novel drug targets to facilitate the development of non-addictive analgesics to treat chronic pain. The endocannabinoid anandamide (AEA) activates cannabinoid receptors while the related lipid palmitoylethanolamide (PEA) serves as an agonist at peroxisome proliferator-activated receptor alpha (PPARα). Activation of cannabinoid receptors by AEA or PPARα receptors by PEA reduces pain, thus positioning modulation of AEA and PEA signaling as an attractive strategy for the development of analgesics. Our group recently identified fatty acid binding protein 5 (FABP5) as an intracellular carrier for AEA and PEA, whose inhibition elevates AEA and PEA levels and produces analgesia. In addition to its expression in the brain, FABP5 is enriched in peripheral sensory neurons and macrophages, positioning it in cell populations that promote pain. Transient receptor potential vanilloid receptor 1 (TRPV1) is an ion channel expressed in peripheral sensory neurons that is essential for inflammatory thermal hyperalgesia and is implicated in diverse pain conditions in humans. Here, we will test the novel hypothesis that FABP5 inhibition potentiates AEA and PEA signaling in sensory neurons to suppress pain by attenuating the sensitization and upregulation of TRPV1 during inflammation. Specific Aim 1 will test the hypothesis that genetic deletion of FABP5 in sensory neurons unmasks analgesic effects mediated by AEA and PEA while its deletion in macrophages suppresses pain by attenuating the pro-inflammatory output of macrophages. To interrogate the mechanisms underlying these effects, Specific Aim 2 will test the hypothesis that TRPV1 sensitization, a process that amplifies inflammatory pain, is suppressed in mice lacking FABP5. We will further determine whether this effect is mediated by augmented AEA and PEA signaling in sensory neurons. Specific Aim 3 will test the hypothesis that FABP5 is essential for TRPV1 upregulation during chronic inflammation. Specifically, we will investigate the molecular mechanisms underlying the control of TRPV1 upregulation by FABP5 in sensory neurons. If successful, the outcome of this work will advance our understanding of pain modulation by FABP5, AEA, and PEA, and will provide a foundation for the development of analgesics targeting FABP5.

慢性疼痛影响三分之一的成年人口，并带来巨大的社会和经济负担。目前的治疗方法通常包括非甾体抗炎药，但其效果有限。且阿片类药物具有显着的成瘾性，因此迫切需要对其进行验证。确定新的药物靶点，以促进非成瘾性镇痛药的开发，以治疗慢性疼痛。内源性大麻素 anandamide (AEA) 激活大麻素受体，而相关脂质棕榈酰乙醇酰胺 (PEA) 是过氧化物酶体增殖物激活受体 α (PPARα) 的激动剂。 AEA 激活大麻素受体或 PEA 激活 PPARα 受体可减轻疼痛，从而定位 AEA 和 PEA 信号传导的调节是我们团队开发镇痛药的一个有吸引力的策略。最近发现脂肪酸结合蛋白 5 (FABP5) 作为 AEA 和 PEA 的细胞内载体，其 FABP5 的抑制作用会提高 AEA 和 PEA 水平并产生镇痛作用。富含外周感觉神经元和巨噬细胞，将其定位于促进疼痛的细胞群中。瞬时受体电位香草酸受体 1 (TRPV1) 是一种在外周感觉中表达的离子通道神经元对于炎症性热痛觉过敏至关重要，并且与多种疼痛状况有关在这里，我们将测试 FABP5 抑制增强 AEA 和 PEA 信号传导的新假设。感觉神经元通过减弱 TRPV1 的敏化和上调来抑制疼痛具体目标 1 将检验感觉神经元中 FABP5 基因缺失揭示的假设。由 AEA 和 PEA 介导的镇痛作用，而其在巨噬细胞中的缺失通过减弱来抑制疼痛巨噬细胞的促炎输出，以探究这些作用的机制。目标 2 将检验 TRPV1 敏化（一种放大炎性疼痛的过程）受到抑制的假设我们将进一步确定这种效应是否是由增强的 AEA 和 PEA 介导的。具体目标 3 将检验 FABP5 对于 TRPV1 至关重要的假设。具体来说，我们将研究其潜在的分子机制。如果成功的话，这项工作的结果将会是感觉神经元中 FABP5 上调的控制。 FABP5、AEA 和 PEA 促进了我们对疼痛调节的理解，并将为以下研究奠定基础：开发针对 FABP5 的镇痛药。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacological Inhibition of Brain Fatty Acid Binding Protein Reduces Ethanol Consumption in Mice.

脑脂肪酸结合蛋白的药理抑制可减少小鼠的乙醇消耗。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Figueiredo, Antonio;Hamilton, John;Marion, Matthew;Blum, Kenneth;Kaczocha, Martin;Haj;Deutsch, Dale;Thanos, Panayotis K
通讯作者：
Thanos, Panayotis K

Truxillic acid monoamides as fatty acid binding protein 5 inhibitors.

Truxillic Acid monoamides 作为脂肪酸结合蛋白 5 抑制剂。

DOI：
发表时间：
2023-10-30
期刊：
影响因子：
3.5
作者：
Zhu, Chuanzhou;Schutz, Livia;Jayanetti, Kalani;Takemura, Kathryn;Doswell, Faniya;Wang, Liqun;Ojima, Iwao;Kaczocha, Martin
通讯作者：
Kaczocha, Martin

Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons.

多巴胺对背根神经节神经元瞬时受体电位香草酸 1 型 (TRPV1) 受体的调节。

DOI：
发表时间：
2016-03-15
期刊：
影响因子：
0
作者：
Chakraborty, Saikat;Rebecchi, Mario;Kaczocha, Martin;Puopolo, Michelino
通讯作者：
Puopolo, Michelino

Presynaptic inhibition of transient receptor potential vanilloid type 1 (TRPV1) receptors by noradrenaline in nociceptive neurons.

去甲肾上腺素对伤害性神经元中瞬时受体电位香草酸 1 型 (TRPV1) 受体的突触前抑制作用。

DOI：
发表时间：
2017-04-15
期刊：
影响因子：
0
作者：
Chakraborty, Saikat;Elvezio, Vincent;Kaczocha, Martin;Rebecchi, Mario;Puopolo, Michelino
通讯作者：
Puopolo, Michelino

Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses.

脂肪酸结合蛋白 5 控制中央谷氨酸突触的逆行内源性大麻素信号传导。

DOI：
发表时间：
2018-03-27
期刊：
影响因子：
11.1
作者：
Haj;Shen, Roh;Elmes, Matthew W;Studholme, Keith;Kanjiya, Martha P;Bogdan, Diane;Thanos, Panayotis K;Miyauchi, Jeremy T;Tsirka, Stella E;Deutsch, Dale G;Kaczocha, Martin
通讯作者：
Kaczocha, Martin