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

描述（由申请人提供）：角膜的化学和热痛主要由称为TRPV1的钙钠渗透性离子通道传导，该离子通道在三叉神经节的细胞体中表达。当损伤（包括手术）或疾病引起炎症时，炎症过程会增加TRPV1离子通道对疼痛刺激的敏感性，这种现象被称为炎症性痛觉过敏。我们的长期目标是了解介导炎症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的关键的第一步。在本研究中，我们将重点研究神经生长因子（NGF）调节TRPV1的分子机制。炎症和损伤导致神经生长因子、胰岛素和胰岛素样生长因子等营养因子的释放，它们通过激活受体酪氨酸激酶（rtk）来增加伤害感受器的兴奋性。有研究认为RTK激活通过磷酸肌肽4,5-二磷酸（PIP2）的水解使TRPV1增敏，从而减轻PIP2对TRPV1的强直抑制。然而，由于新出现的证据表明磷酸肌肽3,4,5-三磷酸（PIPS）可能参与其中，PIP2的作用是有争议的。基于我们的初步数据，我们提出PI3K磷酸化PIP2形成PIP3可能是NGF致敏伤害感受器的重要因素。我们的具体目标是研究NGF调节TRPV1的分子机制和功能意义。了解rtk对TRPV1的调控对于全面了解炎症如何调节角膜伤害感受器的兴奋性以及开发治疗炎症性疼痛的改进疗法至关重要。

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.