Pharmacology and biophysics of the voltage-gated sodium channel Nav1.7: a therape

描述（由申请人提供） 摘要：疼痛一直是医生咨询的最常见原因，慢性疼痛综合征会严重损害患者的生活质量。目前的镇痛药是有限的，因为许多患有慢性疼痛综合征或神经性疼痛的患者对药物没有反应。因此，迫切需要开发新的药物，沿着更好地理解作为这些镇痛剂靶点的蛋白质的机制。电压门控钠通道亚型1.7是一个新兴的镇痛药物开发的目标。使用创新的方法，我计划通过组合的工具，包括化学筛选，结构生物学和电生理学的特点，电压门控钠通道的新的治疗区域。这些研究将为未来镇痛药物的开发以及电压门控钠通道的基本过程提供新的见解。 公共卫生相关性：疼痛是许多疾病的主要症状，慢性疼痛综合征可严重降低生活质量。临床上显然需要具有新作用机制的新型镇痛药。电压门控钠通道亚型1.7（Nav1.7）是镇痛药的新靶点，因为Nav1.7功能缺失突变的患者不会感到疼痛。我的研究计划是通过开发药理学工具和表征电压感知机制来研究Nav1.7。我提出的研究，如果成功的话，将为开发新的镇痛药铺平道路，并进一步了解健康和疾病中电压门控钠通道的电压感知机制。

DESCRIPTION (Provided by the applicant) Abstract: Pain has been the most frequent reason for physician consultation, and chronic pain syndromes can severely undermine patients' qualities of life. Current analgesics are limited in that many patients with chronic pain syndromes or neuropathic pains do not respond to the drugs. Therefore there is a pressing need for new drug development along with a better understanding of the mechanism of the proteins that are the targets of these analgesics. Voltage-gated sodium channel subtype 1.7 is a newly emerging target for analgesic development. Using innovative approaches, I plan to characterize novel therapeutic regions of the voltage-gated sodium channel by a combination of tools, including chemical screening, structural biology, and electrophysiology. The proposed studies will provide new insights into future analgesic development as well as fundamental processes of voltage-gated sodium channels. Public Health Relevance: Pain is a major symptom in many medical conditions and chronic pain syndromes can severely reduce quality of life. There is a clear clinical need for new analgesics with a new mechanism of action. The voltage-gated sodium channel subtype 1.7 (Nav1.7) is a newly emerging target for analgesics, as patients with loss-of-function mutations in Nav1.7 do not feel pain. My research proposal is to study Nav1.7 by developing pharmacological tools and characterizing the mechanism of voltage sensing. My proposed research, if successful, will pave the way for the development of new analgesics and further our understanding of the mechanisms of voltage sensing in voltage-gated sodium channels in health and in disease.