TRP Channel Mediated Pain Circuitry

描述（由申请人提供）：本修订后的PO 1提案的基本目标是了解疼痛和瘙痒是如何由不同的伤害感受器和刺激感受器感觉神经元产生的，并开发可以使相关信号沉默的技术，作为潜在的新型治疗策略。该计划现在完全集中在外周神经系统和瞬时受体电位（TRP）TRPV 1，TRPA 1和TRPV 3通道以及P2 X嘌呤能配体门控离子通道上，因为它们都是感觉信号处理中的关键元素，甚至更重要的是，因为它们都是大孔通道，允许药物分子渗透到神经细胞内部，以阻止兴奋和递质释放。项目1中的Clifford Woolf将通过在通过通道递送永久带电的钠通道阻断剂QX-314后短暂沉默其轴突来鉴定表达疼痛和瘙痒的初级感觉神经元中TRPV 11、TRPV 3、TRPA 1和P2 X3的不同子集的功能。项目2中的布鲁斯比恩还将探索如何通过TRP和嘌呤能配体门控离子通道渗透药物来沉默初级感觉神经元，但通过使用阳离子钙通道阻滞剂来破坏外周中的囊泡释放以减少神经源性炎症和脊髓中的囊泡释放以消除突触传递。大卫Clapham的项目3将确定TRPV 3如何以及在何处导致疼痛和瘙痒（在角质形成细胞或感觉神经元中），这是一个重要的问题，因为TRPV 3拮抗剂在临床前模型中是镇痛剂，并且即将进行临床测试，并且还将探索离子通道阻断剂通过TRPV 3的渗透是否可以用于改变角质形成细胞和初级感觉神经元对疼痛和瘙痒的贡献。项目4中的马秋福将使用基因技术沉默特定的初级感觉神经元，以梳理出它们在疼痛和瘙痒中的特定作用。初级感觉神经元SP

DESCRIPTION (provided by applicant): The fundamental goal of this revised PO1 proposal is to understand how pain and itch are generated by different nociceptor and pruriceptors sensory neurons and to develop techniques that can pharmacologically silence the signals responsible, as a potential novel therapeutic strategy. The program is now entirely focused on the peripheral nervous system and on the Transient Receptor Potential (TRP) TRPV1, TRPA1 and TRPV3 channels and P2X purinergic ligand-gated ion channels, both because they are key elements in the processing of sensory signals, and even more so because they are all large pore channels allowing permeation of drug molecules into the interior of nerve cells to block excitation and transmitter release. Clifford Woolf in Project 1 will identify the function of the different subsets of TRPV1l, TRPV3, TRPA1 and P2X3 expressing primary sensory neurons in pain and itch by transiently silencing their axons after delivery of the permanently charged sodium channel blocker QX-314 through the channels. Bruce Bean in Project 2 will also explore how permeation of drugs through TRP and purinergic ligand-gated ion channels can be used to silence primary sensory neurons, but by using delivery of cationic calcium channel blockers to disrupt vesicle release in the periphery to reduce neurogenic inflammation and in the spinal cord to eliminate synaptic transmission. David Clapham's Project 3 will identify how and where TRPV3 contributes to pain and itch (in keratinocytes or sensory neurons), an important issue since TRPV3 antagonists are analgesic in preclinical models and are about to be tested clinically, and will also explore if permeation of ion channel blockers through TRPV3 can be used to modify the contribution of keratinocytes and primary sensory neurons to pain and itch. Qiufu Ma in Project 4 will use genetic techniques to silence defined primary sensory neurons to tease out their specific role in pain and itch. A primary sensory neuron sp