Inflammatory hyperalgesia due to TRPV1, the pepper spray receptor in the cornea

TRPV1（角膜中的胡椒喷雾受体）引起的炎症性痛觉过敏

• 批准号: 8657437
• 负责人: Sharona E Gordon
• 金额: $ 34.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657437
• 关键词: Address; Adipocytes; Adult; Afferent Neurons; American; Arthritis; Back Pain; Boxing; Cell Differentiation process; Cell Surface Receptors; Cell membrane; Complex; Cornea; Differentiation and Growth; Economics; Enzymes; Family; Funding; Generations; Glucose Transporter; Goals; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Headache; Hour; Hyperalgesia; Image; Inflammation; Inflammatory; Injury; Insulin; Ion Channel; Knowledge; Light; Mediating; Membrane Lipids; Membrane Proteins; Mental Health; Metabolism; Modeling; Molecular; Molecular Biology; Monomeric GTP-Binding Proteins; Muscle; Muscle Cells; NGFR Protein; Nerve Growth Factors; Neurons; Nociceptors; Pain; Patients; Personal Satisfaction; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Plasma; Population; Postoperative Pain; Process; Productivity; Property; Protein-Serine-Threonine Kinases; Public Health; Quality of life; Receptor Cell; Regulation; Reporting; Role; Sensory; Signal Pathway; Signal Transduction; Specificity; Stimulus; Surveys; TRPV1 gene; Testing; Tooth structure; United States National Center for Health Statistics; Work; addiction; base; cancer pain; chronic pain; health economics; inflammatory pain; interest; lost work time; pain receptor; physical conditioning; public health relevance; receptor; response; rho; single molecule; social; stoichiometry; trafficking

DESCRIPTION (provided by applicant): The goal of our work is to elucidate the cellular and molecular mechanisms by which cell-surface receptors regulate the function, trafficking, and expression of ion channels. We are particularly interested in receptor regulation of ion channels in pain transduction, as sensitization to painful stimuli during inflammation (inflammatory hyperalgesia) profoundly influences our physical and mental health, as well as our economic and social well-being. We have chosen the Ca2+-permeable channel TRPV1 as our model both because its properties make it especially suitable and because of its importance in transducing painful stimuli and in tuning the excitability of pain-transducing neurons. Chronic pain is a significant public health and economic problem in the US. An analysis of the 2003 American Productivity Audit, a national survey of US workers, showed that, in a given two-week period, 13% of the workforce lost work time due to uncontrolled pain, with a mean loss of 4.6 hours per week. The 2003 National Center for Health Statistics Report found that 26% of adults report having a problem with pain lasting more than 24 hours. A 2006 study of chronic pain patients found that more than half felt they had little or no control over their pain. Headache, back pain, arthritis pain, tooth pain, cancer pain, and post-operative pain are just a few of the common conditions contributing to decreased quality of life and economic loss across the whole spectrum of the US population. Current treatments are clearly not sufficient to address the wide-spread need for pain relief, and have further problems related to specificity and addiction. Nerve Growth Factor (NGF) was discovered by Rita Levi-Montalcini and Stanley Cohen in the late 1950's. From the first, they understood its power to regulate the differentiation and growth of sensory neurons. NGF is involved in the guidance and survival of sensory neurons and is released onto TRPV1-expressing neurons during injury and inflammation. Our understanding of how NGF sensitizes TRPV1 in inflammatory hyperalgesia exploded in the last several years. In the previous funding period we showed that NGF increases TRPV1 currents by increasing the number of the TRPV1 channels in the plasma membrane. We further showed that a signal-transduction complex is present in nociceptors, composed of the NGF receptor (TrkA), TRPV1, and the enzyme PI3K, which phosphorylates phosphoinositide 4,5-bisphosphate (PIP2) to phosphoinositide 3,4,5-trisphosphate (PIP3). We and others further showed that PI3K activity is required for sensitization. For the remainder of this proposal use the term "sensitization" of TRPV1 to refer to the increase in the number of TRPV1 channels in the plasma membrane. Although cell surface receptor-stimulated trafficking of membrane lipids and membrane proteins is of broad significance to biology, the molecular mechanisms by which it occurs are poorly understood. One of the best-studied examples, trafficking of the Glut4 glucose transporter to the plasma membrane of adipocytes and muscle cells in response to insulin, has revealed a number of important players on which we based our model for NGF-induced trafficking of TRPV1 to the plasma membrane of pain-receptor neurons. Even in adipocytes and muscles, however, many critical steps in this process are not fully understood. Identification of the main players and their interactions in sensitization of TRPV1 may shed light on a signaling pathway essential to cell differentiation, metabolism, and survival in addition to leading to an understanding of TRPV1 regulation important for inflammatory pain.

描述(申请人提供)：我们工作的目标是阐明细胞表面受体调节离子通道的功能、运输和表达的细胞和分子机制。我们对疼痛传导中离子通道的受体调节特别感兴趣，因为炎症(炎症性痛敏)过程中对疼痛刺激的敏化深刻地影响着我们的身心健康，以及我们的经济和社会福祉。我们选择钙离子渗透通道TRPV1作为我们的模型，既是因为它的特性使其特别适用，也是因为它在传递疼痛刺激和调节疼痛传导神经元的兴奋性方面具有重要意义。在美国，慢性疼痛是一个重大的公共健康和经济问题。对2003年美国生产力审计的一项分析显示，在给定的两周期间，13%的劳动力因疼痛失控而失去工作时间，平均每周损失4.6个小时。2003年国家健康统计中心的报告发现，26%的成年人报告疼痛持续时间超过24小时。2006年对慢性疼痛患者的一项研究发现，超过一半的人认为他们几乎或根本无法控制自己的疼痛。头痛、背痛、关节炎痛、牙痛、癌症痛和术后疼痛只是导致整个美国人口的生活质量下降和经济损失的几种常见疾病。目前的治疗方法显然不足以满足广泛存在的缓解疼痛的需求，而且还存在与特异性和成瘾有关的进一步问题。神经生长因子是由Rita Levi-Montalcini和Stanley Cohen在20世纪50年代末的S发现的，他们从一开始就了解了神经生长因子调节感觉神经元分化和生长的能力。NGF参与感觉神经元的引导和存活，并在损伤和炎症过程中释放到表达TRPV1的神经元上。我们对NGF如何在炎症性痛觉过敏中增敏TRPV1的理解在过去几年里出现了爆炸性的变化。在之前的资助期间，我们发现NGF通过增加质膜上TRPV1通道的数量来增加TRPV1电流。我们进一步证明在伤害性感受器中存在一个信号转导复合体，它由NGF受体(TrkA)、TRPV1和PI3K酶组成，PI3K酶将磷脂酰肌醇4，5-二磷酸(PIP2)磷酸化成3，4，5-三磷酸(PIP3)。我们和其他人进一步证明了PI3K活性是致敏所必需的。在本提案的其余部分中，使用术语“TRPV1的敏化”来指质膜中TRPV1通道数量的增加。尽管细胞表面受体刺激的膜脂和膜蛋白的转运在生物学上具有广泛的意义，但其发生的分子机制却知之甚少。GLUT4葡萄糖转运体在胰岛素作用下转运到脂肪细胞和肌肉细胞的质膜，这是研究得最好的例子之一，揭示了许多重要的作用，我们的模型以NGF诱导的TRPV1到痛觉感受器神经元的质膜转运为基础。然而，即使在脂肪细胞和肌肉中，这一过程中的许多关键步骤也没有被完全理解。识别TRPV1致敏过程中的主要角色及其相互作用，不仅有助于了解TRPV1对炎性疼痛的重要调控，还可能有助于揭示细胞分化、代谢和生存所必需的信号通路。