Sodium channels and electrogenesis in sensory neurons

 描述(由申请人提供)：疼痛可能是一个严重的医疗问题。虽然背根神经节(DRG)感觉神经元的超兴奋性经常导致神经病理性和炎症性疼痛，但这种超兴奋性背后的细胞和分子变化尚不完全清楚。这种知识的缺乏阻碍了更好的疗法的发展。研究表明，炎症和神经损伤会改变钠通道的特性。我们有令人信服的证据表明，复苏性电流活动增加与感觉神经元的异常电兴奋性有关，并与遗传性和获得性疼痛综合征有关。虽然这些电流是神经元自发和高频放电的关键决定因素，但我们对感觉神经元中调节它们的分子机制的了解还不完全。我们已经开发了体内和体外的方法来操纵参与复活电流产生的蛋白质，这使得我们能够独特地定位于研究这些电流在感觉神经元功能中的作用。在这个项目中 我们建议：1)确定Nav？4亚基和成纤维细胞生长因子同源因子(FHFs)如何调节DRG神经元的复苏性电流。2)确定再生电流产生的关键分子决定因素。3)明确河豚毒素受体和S复苏电流在慢性压迫性损伤、奥沙利铂所致神经病和遗传性小纤维神经病中的作用。4)确定大麻素是否可以优先靶向感觉神经元的复苏性电流。这项研究将为如何调控复苏的钠电流以及如何操纵它们提供基本的见解，增加我们对疼痛的细胞和分子机制的了解，并促进疼痛和其他细胞兴奋性障碍的新疗法的发现。

 DESCRIPTION (provided by applicant): Pain can be a serious medical problem. While it is firmly established that hyper excitability of dorsal root ganglion (DRG) sensory neurons often contributes to neuropathic and inflammatory pain, the cellular and molecular changes that underlie this hyper excitability are not fully understood. This lack of knowledge has hindered the development of better therapeutics. Studies indicate that sodium channel properties are altered by inflammation and nerve injury. We have compelling evidence that increased resurgent current activity is involved in abnormal electrical excitability in sensory neurons, and in inheritd and acquired pain syndromes. Although these currents are crucial determinants of spontaneous and high-frequency firing in neurons, our understanding of the molecular mechanisms that regulate them in sensory neurons is incomplete. We have developed in vivo and in vitro approaches for manipulating proteins involved in resurgent current generation that uniquely positions us to investigate the roles of these currents in sensory neuron function. In this project we propose to 1) Determine how the Navß4 subunit and Fibroblast Growth Factor Homologous Factors (FHFs) regulate resurgent currents in DRG neurons. 2) Determine crucial molecular determinants of resurgent current generation. 3) Identify the roles of TTX-R and TTX-S resurgent currents in chronic constriction injury (CCI), oxaliplatin-induced neuropathy and inherited small fiber neuropathy. 4) Determine if cannabinoids can preferentially target resurgent currents in sensory neurons. This research will provide fundamental insight into how resurgent sodium currents are regulated and how they can be manipulated, increasing our knowledge of cellular and molecular mechanisms of pain and facilitating the discovery of new therapeutics for pain and other disorders of cellular excitability.