Role of the DSC1 family of cation channels in insect neurophysiology and neurotox

描述（由申请人提供）：使用杀虫剂和驱避剂控制昆虫病媒是对抗一些最具破坏性的人类疾病（如疟疾）的重要策略。今天使用的许多杀虫剂和驱虫剂针对昆虫神经系统的组成部分，如电压门控钠通道和嗅觉系统。20年前，从黑腹果蝇（Drosophila melanogaster）中克隆出了一个类似钠通道的基因，称为DSC 1（果蝇钠通道1）。尽管近二十年来，基于其与钠通道的序列相似性，DSC 1被认为编码电压门控钠通道，但我们最近发现DSC 1及其在蟑螂中的直向同源物BSC 1编码电压门控阳离子通道新家族的创始成员。我们最近的基因敲除实验表明，DSC 1在调节D。这表明DSC 1家族的阳离子通道在昆虫神经生理学和毒理学中起着重要作用。该项目的长期目标是全面了解DSC 1家族阳离子通道在调节昆虫神经元回路和对杀虫剂，引诱剂和驱避剂的敏感性中的作用。将采取综合的分子、电生理、药理学和遗传学方法来实现这一目标。拟议的资助期的具体目标是：1）阳离子通道的DSC 1家族的分子和电生理表征; 2）确定阳离子通道的DSC 1家族在昆虫化学感觉和神经毒理学中的作用;和3）理解DSC 1通道在调节特定神经回路中的作用。这一基础研究将增强我们对新发现的离子通道家族在昆虫神经生理学和毒理学中的作用的基础知识。研究结果可为未来开发新一代杀虫剂或提高目前使用的杀虫剂、引诱剂或驱避剂效力的新方法提供基础。迫切需要制定有效控制包括疟疾在内的人类疾病昆虫媒介的新战略。该建议旨在了解一个新的昆虫离子通道家族在神经生理学和神经毒理学中的作用。这项研究有可能为未来开发新一代杀虫剂或新方法提供基础，以提高目前使用的杀虫剂，引诱剂或驱避剂的功效。

DESCRIPTION (provided by applicant): Use of insecticides and repellents to control insect vectors is an important strategy for fighting some of the most devastating human diseases, such as malaria. Many insecticides and insect repellents used today target components of the insect nervous system, such as voltage-gated sodium channels and the olfaction system. Two decades ago, a sodium channel-like gene, called DSC1 (Drosophila sodium channel 1), was cloned from Drosophila melanogaster. Although for nearly two decades DSC1 had been thought to encode a voltage-gated sodium channel based on its sequence similarity to sodium channels, we recently showed that DSC1 and its orthologue in cockroach, BSC1, encode the founding members of a novel family of voltage-gated cation channels. Our recent gene knockout experiments suggest that DSC1 plays a crucial role in modulating D. melanogaster sensitivity to DEET (an insect repellent) and deltamethrin (a pyrethroid insecticide), implicating DSC1-family cation channels as important players in insect neurophysiology and toxicology. The long-term goal of this project is to reach a comprehensive understanding of the role of the DSC1 family of cation channels in modulating insect neuronal circuitry and sensitivity to insecticides, attractants, and repellents. An integrated molecular, electrophysiological, pharmacological, and genetic approach will be taken to achieve this goal. Specific aims of the proposed grant period are: 1) molecular and electrophysiological characterization of the DSC1 family of cation channels; 2) determination of the role of the DSC1 family of cation channels in insect chemosensation and neurotoxicology; and 3) understanding the role of the DSC1 channel in modulating specific neural circuits. This basic research should enhance our fundamental knowledge of the role of a newly discovered family of ion channels in insect neurophysiology and toxicology. Results could provide a basis for future development of a new generation of insecticides or new methods to enhance the efficacy of currently used insecticides, attractants, or repellents. PUBLIC HEALTH RELEVANCE Development of new strategies for effective control of insect vectors of human diseases, including malaria, is urgently needed. This proposal is aimed at understanding the role of a new family of insect ion channels in neurophysiology and neurotoxicology. This research has the potential to provide a basis for future development of a new generation of insecticides or new methods to enhance the efficacy of currently used insecticides, attractants, or repellents.