Molecular mechanisms of action and resistance of sodium channel-targeting insecti

描述（由申请人提供）：本研究的长期目标是了解两类重要杀虫剂（拟除虫菊酯和钠通道阻滞剂杀虫剂（SCBI））的分子作用和抗性机制。控制重大公共卫生问题的节肢动物害虫的战略仍然严重依赖于使用相对安全的杀虫剂。目前，拟除虫菊酯是用于疟疾控制的杀虫剂处理过的蚊帐（ITNs）中使用的唯一一类杀虫剂，这是由于其快速作用、高效性和对人类的相对低毒性。然而，持续使用拟除虫菊酯的一个主要威胁是产生抗药性。茚虫威及其活性代谢物（DCJW）是一类新SCBI的第一个成员，也符合病媒控制标准，可能是拟除虫菊酯的替代杀虫剂。拟除虫菊酯和茚虫威都以电压门控钠通道为目标;然而，在分子水平上对其作用模式还没有很好的了解，这是表征抗性机制的主要障碍。该更新提案的具体目标是：1）拟除虫菊酯作用和抗性的分子基础表征，以及2）茚虫威/DCJW对钠通道的受体位点和分子作用的鉴定。分子，电生理学和计算机建模方法的组合将被用来测试新的假设，最终目标是定义难以捉摸的拟除虫菊酯和茚虫威受体位点的昆虫钠通道的分子身份。从这一基础研究中获得的新知识将对未来制定有效的监测和管理策略以控制威胁人类健康的主要节肢动物害虫产生重大影响。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular action and resistance mechanisms of two important classes of insecticides, pyrethroids and sodium channel blocker insecticides (SCBIs). Strategies for the control of arthropod pests of major public health concerns continue to rely heavily on the use of relatively safe insecticides. Currently, pyrethroids are the only class of insecticides used in insecticide treated nets (ITNs) for malaria control, due to their fast acting, high efficacy, and relative low toxicity to humans. However, a major threat to the sustained use of pyrethroids is the development of resistance. Indoxacarb and its active metabolite (DCJW), the first member of a new class of SCBIs, also meets vector control criteria, and could be an alternative insecticide to pyrethroids. Both pyrethroids and indoxacarb target voltage-gated sodium channels; however, the modes of their action are not well understood at the molecular level, which presents a major obstacle to the characterization of mechanisms of resistance. The specific aims of this renewal proposal are: 1) Characterization of the molecular basis of pyrethroid action and resistance, and 2) Identification of the receptor site and molecular action of indoxacarb/DCJW on sodium channels. A combination of molecular, electrophysiological, and computer modeling methods will be used to test novel hypotheses, with the final goal of defining the molecular identities of the elusive pyrethroid and indoxacarb receptor sites on the insect sodium channel. New knowledge gained from this fundamental research will have significant impact on future development of effective monitoring and management strategies for controlling major human health-threatening arthropod pests.