Targeting steroid hormone signaling in Anopheles mosquitoes for malaria control

 描述（由申请人提供）：传播疟疾，蚊子媒介不仅必须成功交配、进食和繁殖，而且还必须能够维持疟原虫寄生虫的性生活阶段和几轮增殖分裂。在这个项目中，我们将研究类固醇激素20-羟基蜕皮激素（20 E）在调节昆虫学参数中的作用，这些参数对主要非洲热带疟疾媒介冈比亚按蚊的持续疾病传播至关重要。在成年安。与其他吸血蚊子一样，冈比亚的雌性蚊子在其卵巢中合成20 E，以响应脊椎动物的血餐。此外，安。冈比亚雄性也在其射精中合成大量的20 E，并在交配期间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。来自我们研究小组的越来越多的初步数据表明，性转移的20 E在介导与疟原虫传播相关的成年蚊子生理和行为成分方面发挥着更为普遍的作用。我们已经确定，女性积极选择与男性交配的显着更高水平的20 E在他们的男性生殖附属腺（MAG）;男性20 E的性转移激活女性的途径，影响疟原虫的发展;和应用合成的非甾体20 E激动剂触发一个强大的寿命缩短和绝育效果在女性安。冈比亚和破坏疟原虫的发展。在这里，我们将大大扩展这些初步研究，以解开男性20 E在调节化学和声学过程中的作用，男性交配成功的关键（目标1），确定男性20 E的分子途径调节人类恶性疟原虫的发展（目标2）的贡献，并验证使用20 E激动剂作为蚊子和疟疾控制剂（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战略。

 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.