FABPs: Novel Roles in Pain and Inflammation

FABP：在疼痛和炎症中的新作用

• 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
• 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

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.

慢性疼痛影响了三分之一的成年人口，并带来了巨大的社会和经济负担。

项目成果

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
• 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.

• 发表时间: 2018-10
• 期刊: SEJ surgery and pain
• 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