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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：
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，并造成巨大的社会和经济负担。目前的治疗方法通常包括非甾体类抗炎药，其具有有限的抗炎作用。疗效和阿片类药物，具有显着的成瘾倾向。因此，迫切需要确定新的药物靶点，以促进非成瘾性镇痛药的开发，以治疗慢性疼痛。的内源性大麻素anandamide（AEA）激活大麻素受体，而相关的脂质棕榈酰乙醇胺（PEA）作为过氧化物酶体增殖物激活受体α（PPARα）的激动剂。通过AEA激活大麻素受体或通过PEA激活PPARα受体可减轻疼痛，从而定位 AEA和PEA信号的调节作为镇痛药开发的一个有吸引力的策略。我们集团最近鉴定的脂肪酸结合蛋白5（FABP5）作为AEA和PEA的细胞内载体，其抑制提高AEA和PEA水平并产生镇痛作用。除了在大脑中的表达，FABP5 富含外周感觉神经元和巨噬细胞，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）是一种在外周感觉神经元中表达的离子通道，神经元是炎性热痛觉过敏所必需的，并与多种疼痛状况有关，人类在这里，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炎症具体目标1将检验感觉神经元中FABP5的遗传缺失揭示 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疼痛来抑制疼痛巨噬细胞的促炎物质为了探究这些效应的潜在机制，目的2将检验TRPV1致敏（一种放大炎性疼痛的过程）被抑制的假设缺乏FABP5的小鼠。我们将进一步确定这种作用是否是由增强的AEA和PEA介导的感觉神经元的信号。具体目标3将检验FABP 5对TRPV 1至关重要的假设在慢性炎症期间上调。具体来说，我们将研究潜在的分子机制， FABP5对感觉神经元中TRPV1上调的控制。如果成功，这项工作的成果将推进我们对FABP5、AEA和PEA疼痛调节的理解，并将为开发针对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）

SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents.

作为下一代抗伤害药的新型特鲁西酸单酯脂肪酸结合蛋白抑制剂的 SAR 研究。

DOI：
10.1016/j.bioorg.2022.106184
发表时间：
2022
期刊：
Bioorganic chemistry
影响因子：
5.1
作者：
Wang,Hehe;Taouil,Adam;Awwa,Monaf;Clement,Timothy;Zhu,Chuanzhou;Kim,Jinwoo;Rendina,Dominick;Jayanetti,Kalani;Maharaj,Atri;Wang,Liqun;Bogdan,Diane;Pepe,Antonella;Kaczocha,Martin;Ojima,Iwao
通讯作者：
Ojima,Iwao

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：
10.17756/jrdsas.2017-037
发表时间：
2017
期刊：
Journal of reward deficiency syndrome and addiction science
影响因子：
0
作者：
Antonio Figueiredo;John Hamilton;M. Marion;K. Blum;M. Kaczocha;S. Haj;D. Deutsch;P. Thanos
通讯作者：
P. Thanos

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

DOI：
发表时间：
2018-10
期刊：
SEJ surgery and pain
影响因子：
0
作者：
K. Blum;W. Jacobs;E. Modestino;N. Dinubile;D. Baron;T. McLaughlin;D. Siwicki;Igor Elman;M. Moran;E. Braverman;P. Thanos;R. Badgaiyan
通讯作者：
K. Blum;W. Jacobs;E. Modestino;N. Dinubile;D. Baron;T. McLaughlin;D. Siwicki;Igor Elman;M. Moran;E. Braverman;P. Thanos;R. Badgaiyan

Endocannabinoid metabolism and transport as targets to regulate intraocular pressure.

DOI：
10.1016/j.exer.2020.108266
发表时间：
2020-12
期刊：
Experimental eye research
影响因子：
3.4
作者：
Miller S;Daily L;Dharla V;Gertsch J;Malamas MS;Ojima I;Kaczocha M;Ogasawara D;Straiker A
通讯作者：
Straiker A

FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain.

DOI：
10.1038/s41598-022-13284-0
发表时间：
2022-06-02
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Bogdan, Diane M.;Studholme, Keith;DiBua, Adriana;Gordon, Chris;Kanjiya, Martha P.;Yu, Mei;Puopolo, Michelino;Kaczocha, Martin
通讯作者：
Kaczocha, Martin