Targeting steroid hormone signaling in Anopheles mosquitoes for malaria control

 描述(申请人提供)：要传播疟疾，不仅蚊子媒介必须成功交配、取食和繁殖，而且还必须能够维持疟原虫在有性生活期和几轮繁殖期的分裂。在这个项目中，我们将研究类固醇激素20-羟基蜕皮酮(20E)在调节关键的昆虫学参数中的作用，这些参数对于非洲热带疟疾主要媒介冈比亚按蚊的疾病持续传播至关重要。在成虫An.冈比亚按蚊和其他食血蚊子一样，20E由雌性蚊子在卵巢中合成，对脊椎动物的血液做出反应。此外，An.雄冈比亚也会在其射精中合成大量的20E，并在交配过程中转移这种类固醇激素，启动对雌性生殖健康至关重要的信号级联反应。来自我们研究小组的越来越多的初步数据表明，性转移的20E在调节成年蚊子生理和行为的组成部分方面发挥着更普遍的作用，这些成分也与疟原虫的传播有关。我们已经确定，雌性主动地选择与其雄性生殖附属腺(MAG)中20E水平显著较高的雄性交配；雄性20E的性转移激活了影响疟原虫发育的雌性途径；合成的非类固醇20E激动剂的应用在雌性AN中触发了有效的缩短寿命和绝育效果。冈比亚和破坏疟原虫的发育。在这里，我们将大大扩展这些初步研究，以揭示男性20E在调节对男性交配成功至关重要的化学和声音过程中的作用(目标1)，确定男性20E在调控人类疟疾寄生虫恶性疟原虫发育的分子途径中的贡献(目标2)，并验证20E激动剂作为蚊子和疟疾控制剂的使用(目标3)。通过结合行为、分子和基因组工具，我们的项目将填补蚊子生物学方面的关键知识空白，并将产生新的工具，可用于旨在消除疟疾的蚊子控制策略。

 DESCRIPTION (provided by applicant): To transmit malaria, not only must the mosquito vector mate, feed and reproduce successfully, but it must also be able to sustain the Plasmodium parasite through its sexual life-stages and several rounds of multiplicative division. In this project we will study the role of the steroid hormone 20-hydroxyecdysone (20E) in regulating entomological parameters critical for continued disease transmission in the major Afro-tropical malaria vector Anopheles gambiae. In adult An. gambiae, like in other hematophagous mosquitoes, 20E is synthesized by females in their ovaries in response to a vertebrate blood meal. Moreover, An. gambiae males also synthesize significant quantities of 20E in their ejaculate and transfer this steroid hormone during copulation, initiating signaling cascades critical for female reproductive fitness. Increasing preliminary data from our research group indicates that sexually transferred 20E plays a far more pervasive role in mediating components of adult mosquito physiology and behavior that are also relevant to Plasmodium transmission. We have determined that females actively choose to mate with males with significantly higher levels of 20E in their male reproductive accessory glands (MAGs); that the sexual transfer of male 20E activates female pathways that impact Plasmodium development; and that application of synthetic non-steroidal 20E agonists triggers a potent life-shortening and sterilizing effect in female An. gambiae and disrupts Plasmodium development. Here we will considerably expand on these preliminary studies to unravel the role of male 20E in modulating chemical and acoustic processes critical for male mating success (Aim 1), determine the contribution of male 20E to molecular pathways regulating the development of the human malaria parasite Plasmodium falciparum (Aim 2), and validate the use of 20E agonists as mosquito and malaria control agents (Aim 3). By combining behavioral, molecular and genomic tools, our project will fill in critical knowledge gaps in mosquito biology and will produce new tools that can be exploited in mosquito control strategies aimed at the elimination of malaria.