The Capsaicin Receptor TRPV1, a Novel Target for Omega-3 Fatty Acids

辣椒素受体 TRPV1，Omega-3 脂肪酸的新靶点

• 批准号: 7382525
• 负责人: Jose Matta
• 金额: $ 0.88万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382525
• 关键词: Acute; Adjuvant; Adverse effects; Afferent Neurons; Agonist; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arrhythmia; Atherosclerosis; Attenuated; Autoimmune Process; Behavior; Binding; Binding Sites; Blood Vessels; C Fiber; Calcitonin Gene-Related Peptide; Calcium; Capsaicin; Cardiovascular Diseases; Cardiovascular system; Cations; Cells; Characteristics; Condition; Data; Detergents; Disease; Down-Regulation; Drug Interactions; Eicosanoids; Elasticity; Esthesia; Fatty Acids; Goals; Hand; Healthcare; Heart Diseases; Heating; In Vitro; Inflammatory; Injection of therapeutic agent; Ion Channel; Lead; Length; Ligands; Lipids; Location; Measures; Mediating; Medicine; Membrane; Membrane Fluidity; Micelles; Molecular; Molecular Target; Mus; N-3 polyunsaturated fatty acid; Narcotics; Nature; Nerve; Neurons; Neuropeptides; Nociception; Object Attachment; Omega-3 Fatty Acids; Pain; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Physiological; Physiology; Play; Property; Protein Isoforms; Proteins; Protons; Public Health; RBBP9 gene; Regulation; Role; Sensory Nerve Endings; Signal Pathway; Signal Transduction; Site; Stimulus; System; Testing; Therapeutic; Tissues; Trachea; Translating; Treatment Efficacy; Triton X100; United States Environmental Protection Agency; Vanilloid; Vasodilation; afferent nerve; behavior test; capsaicin receptor; cardiovascular disorder prevention; fluidity; in vivo; in vivo Model; inflammatory pain; latent nuclear antigen; novel; novel strategies; octylglucopyranoside; receptor; response; sensor

DESCRIPTION (provided by applicant): The capsaicin receptor or transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel that plays a critical role in inflammatory pain signaling and vascular physiology. TRPV1 is a molecular sensor of inflammatory pain and its multimodal properties for activation enable neuronal integration of a variety of noxious stimuli such as heat, low pH and inflammatory eicosanoids. Although TRPV1 is implicated in pain sensation, this protein also serves as an imprtant regulator of vascular physiology by inducing neuropeptide release and consequently, vasodilation. Thus partial agonists with low intrisic efficacy may serve as blockers of TRPV1-mediated pain, as well as promote the release of neuropeptides to allow vasodilation and positive vascular effects. Interestingly, omega-3 polyunsaturated fatty acids (n-3 PUFAs) appear to have pronounced analgesic properties, positive vascular effects, and are implicated in the prevention of cardiac diseases, such as atherosclerosis, cardiac arrhythmias and various inflammatory and autoimmune conditions. Our recent data suggests a selective up- and down-regulation of TRPV1 by n-3 fatty acids. The long-term goal of this proposal is to determine whether the cardiovascular benefits and analgesic properties of n-3 PUFAs may be in part elicited via an interaction with TRPV1. By understanding the interactions between n-3 PUFAs and TRPV1, novel therapies for inflamatory pain and certain cardivascular diseases may develop. This study will determine how n-3 PUFAs regulate TRPV1 and the physiological relevance of this mechanism in vivo. Electrophysiological recordings from single cells expressing the TRPV1 channel will determine the molecular mechanism for TRPV1 modulation by n-3 PUFAs. The potential cardiovascular benefits of n-3 PUFAs will be studied by measuring TRPV1-mediated release of neuropeptides from sensory nerves. The analgesic properties of n-3 PUFAs will be tested with a capsaicin-evoked pain-related behavior test in mice. The proposed study will further our understanding of n- 3 PUFAs as a therapeutic approach to cardiac diseases and inflammatory pain, two major public health problems in our nation which usually accompany each other. Alternatives or adjuvants to narcotics and non- steroidal anti-inflammatory drugs for the treatment of pain is a high priority due to the addictive, toxic, and drug-drug interaction properties of these medicines. Thus, TRPV1 may serve as a new molecular target for n-3 PUFAs and provide a novel approach in the treatment of cardivascular diseases and pain,

描述（由申请人提供）：辣椒素受体或瞬时受体电位香草酸亚型 1 (TRPV1) 是一种非选择性阳离子通道，在炎症疼痛信号传导和血管生理学中发挥着关键作用。 TRPV1 是一种炎症性疼痛的分子传感器，其激活的多模式特性使神经元能够整合各种有害刺激，例如热、低 pH 值和炎症类二十烷酸。尽管 TRPV1 与痛觉有关，但这种蛋白质还可以通过诱导神经肽释放并最终导致血管舒张，从而充当血管生理学的重要调节剂。因此，具有低内在功效的部分激动剂可以作为 TRPV1 介导的疼痛的阻断剂，以及促进神经肽的释放以允许血管舒张和积极的血管效应。有趣的是，omega-3 多不饱和脂肪酸 (n-3 PUFA) 似乎具有显着的镇痛特性、积极的血管作用，并且与预防心脏疾病有关，例如动脉粥样硬化、心律失常以及各种炎症和自身免疫性疾病。我们最近的数据表明 n-3 脂肪酸选择性上调和下调 TRPV1。该提案的长期目标是确定 n-3 PUFA 的心血管益处和镇痛特性是否部分是通过与 TRPV1 的相互作用引起的。通过了解 n-3 PUFA 和 TRPV1 之间的相互作用，可能会开发出治疗炎症性疼痛和某些心血管疾病的新疗法。这项研究将确定 n-3 PUFA 如何调节 TRPV1 以及该机制在体内的生理相关性。表达 TRPV1 通道的单细胞的电生理记录将确定 n-3 PUFA 调节 TRPV1 的分子机制。将通过测量 TRPV1 介导的感觉神经神经肽的释放来研究 n-3 PUFA 的潜在心血管益处。 n-3 PUFA 的镇痛特性将通过小鼠辣椒素诱发的疼痛相关行为测试进行测试。拟议的研究将进一步加深我们对 n-3 PUFA 作为治疗心脏病和炎性疼痛的方法的理解，这两个疾病是我国通常相互伴随的两个主要公共卫生问题。由于麻醉药和非甾体抗炎药的成瘾性、毒性和药物间相互作用的特性，用于治疗疼痛的麻醉药和非甾体抗炎药的替代品或佐剂是高度优先考虑的。因此，TRPV1可能作为n-3 PUFA的新分子靶标，并为治疗心血管疾病和疼痛提供新方法。