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

描述(申请人提供)：本研究的长期目标是了解拟除虫菊酯和钠通道阻滞剂这两类重要杀虫剂的分子作用和抗药性机制。控制主要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，拟除虫菊酯类杀虫剂是用于控制疟疾的杀虫剂处理网(ITN)中唯一使用的杀虫剂，因为它们作用迅速、高效，对人类的毒性相对较低。然而，对持续使用拟除虫菊酯的一个主要威胁是产生抗药性。Indoxacarb及其活性代谢产物(DCJW)是一类新的拟除虫菊酯类杀虫剂中的第一个成员，也符合媒介控制标准，可以作为拟除虫菊酯的替代杀虫剂。拟除虫菊酯和吲哚杀威都是以电压门控钠通道为靶标的；然而，它们的作用模式在分子水平上还不是很清楚，这是表征抗性机制的主要障碍。这一更新建议的具体目的是：1)表征拟除虫菊酯作用和抗性的分子基础，以及2)鉴定吲哚杀威/DCJW在钠通道上的受体位置和分子作用。将使用分子、电生理学和计算机模拟方法的组合来检验新的假设，最终目标是确定昆虫钠通道上难以捉摸的拟除虫菊酯和吲哚杀威受体位置的分子身份。从这项基础性研究中获得的新知识将对今后制定有效的监测和管理战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.