Inflammatory hyperalgesia mediated by TRPV1, the pepper spray receptor in cornea

TRPV1（角膜中的胡椒喷雾受体）介导的炎症性痛觉过敏

• 批准号: 7487744
• 负责人: Sharona E Gordon
• 金额: $ 37.11万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487744
• 关键词: 1-Phosphatidylinositol 4-Kinase; Address; Afferent Neurons; Amino Acids; Antibodies; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; C-terminal; Calcium; Cell membrane; Cells; Chemicals; Co-Immunoprecipitations; Confocal Microscopy; Cornea; Corneal Injury; Data; Development; Disruption; Elements; Fluorescence; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Goals; Hybrids; Hydrolysis; Hyperalgesia; Inflammation; Inflammatory; Injury; Insulin; Ion Channel; Kinetics; Lead; Lipids; Localized; Measures; Mediating; Membrane; Modeling; Molecular; N-terminal; Nerve Growth Factors; Neurons; Nociceptors; Operative Surgical Procedures; Opiates; PH Domain; PTGS2 gene; Pain; Pain management; Peptides; Peripheral; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Phosphotyrosine; Point Mutation; Process; Production; Protein Binding Domain; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Recombinants; Regulation; Research Personnel; Role; Safety; Signal Transduction; Sodium; Somatomedins; Specificity; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; Surface; TRPV1 gene; Testing; Tyrosine; Tyrosine Phosphorylation; Yeasts; aging population; base; direct application; improved; inflammatory pain; inhibitor/antagonist; mutant; neuronal cell body; novel; prevent; programs; receptor; research study; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): Chemical and thermal pain in the cornea is primarily transduced by a calcium- and sodium-permeable ion channel called TRPV1 expressed in nociceptors with cell bodies in the trigeminal ganglia. When injury (including surgery) or illness cause inflammation, the inflammatory process increases the sensitivity of TRPV1 ion channels to painful stimuli, a phenomenon known as inflammatory hyperalgesia. Our long-term goal is to understand the molecular mechanisms mediating inflammatory hyperalgesia, a critical first step in developing more effective pain therapies for corneal injury. In this study, we will focus on the molecular mechanisms of TRPV1 modulation by Nerve Growth Factor (NGF). Inflammation and injury lead to release of trophic factors such as NGF, insulin, and Insulin-like Growth Factor, which increase nociceptor excitability by activating receptor tyrosine kinases (RTKs). It has been proposed that RTK activation sensitizes TRPV1 through hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2), relieving a tonic inhibition of TRPV1 by PIP2. The role of PIP2 is controversial, however, due to emerging evidence that phosphoinositide 3,4,5- trisphosphate (PIPS) may be involved. Based on our preliminary data, we propose that phosphorylation of PIP2 by phosphoinositide 3-kinase (PI3K) to form PIP3 may be an essential element of nociceptor sensitization by NGF. Our specific aims will address the molecular mechanism and functional significance of TRPV1 modulation by NGF. Understanding the regulation of TRPV1 by RTKs is critical to a complete understanding of how inflammation modulates corneal nociceptor excitability and to the development of improved therapies to treat inflammatory pain.

描述（由申请人提供）：角膜中的化学和热疼痛主要由三叉神经节中具有细胞体的伤害感受器中表达的称为TRPV 1的钙和钠渗透性离子通道转导。当损伤（包括手术）或疾病引起炎症时，炎症过程会增加TRPV 1离子通道对疼痛刺激的敏感性，这种现象称为炎症性痛觉过敏。我们的长期目标是了解介导炎性痛觉过敏的分子机制，这是开发更有效的角膜损伤疼痛治疗方法的关键第一步。在这项研究中，我们将集中在神经生长因子（NGF）的TRPV 1调制的分子机制。炎症和损伤导致营养因子如NGF、胰岛素和胰岛素样生长因子的释放，其通过激活受体酪氨酸激酶（RTK）来增加伤害感受器兴奋性。已经提出RTK活化通过水解磷酸肌醇4，5-二磷酸（PIP 2）来敏化TRPV 1，从而缓解PIP 2对TRPV 1的紧张性抑制。然而，PIP 2的作用是有争议的，由于新出现的证据表明磷酸肌醇3，4，5-三磷酸（PIPS）可能参与其中。基于我们的初步数据，我们提出磷酸肌醇3-激酶（PI 3 K）磷酸化PIP 2形成PIP 3可能是NGF致敏伤害感受器的重要因素。我们的具体目标是阐明神经生长因子调节TRPV 1的分子机制和功能意义。了解RTKs对TRPV 1的调节对于全面了解炎症如何调节角膜伤害感受器兴奋性以及开发治疗炎症性疼痛的改进疗法至关重要。