Molecular Basis of Ecdysteroid Action in the Mosquito

摘要： 吸血的雌性蚊子传播许多毁灭性的疾病， 人血足够大的血餐对于雌性的卵子发育是必不可少的 蚊子，从而相互关联的繁殖，吸血和病原体传播。因此，我们认为， 对调控卵子发育的分子机制的清楚理解， 在蚊子控制方法的进步中发挥着关键作用。埃及伊蚊登革热寨卡病毒 和传播黄热病的蚊子，两种主要的昆虫激素-保幼激素（JH） 和20-羟基蜕皮激素（20 E）控制双相雌蚊生殖周期。的 卵孵化后（PE）或卵黄发生前成熟期受JH控制， 倍半萜然而，大多数情况下，血餐后（PBM）或卵黄发生期 由蜕皮激素20 E控制。JH作用的分子基础的某些方面已经被 在最近的时间解密。然而，关于中间因素在这一过程中的作用的研究， JH/Met调节级联反应正在进行中。在大多数情况下，JH的基因激活是由 直接DNA结合的JH-受体甲氧普仑耐受（Met）。然而，镇压 JH的机制是间接的，通过中间因素。该提案旨在进一步 阐明JH介导的基因激活和阻遏级联。角色调查 Krüppel同源物1（Kr-h1），作为Met的下游因子介导基因阻遏，和 它与长距离阻遏物Hairy的协同作用将是主要焦点之一。的 建议对JH通路靶基因的染色质景观进行比较分析， 确定染色质上的组分如Met、Hairy和Kr-h1的贡献 目标基因的状态。大多数关于20 E作用机制的研究都集中在 通过蜕皮激素受体（EcR）进行正基因调控。这项建议主要是针对 破译20 E和EcR在以前未探索的负基因调控领域的作用， 在卵黄发生期。我们计划阐明直接和间接负性的机制， 调节和鉴定20 E/ECR介导基因的共阻遏物和中间因子 阻遏途径这项研究可能会导致确定目标， 被阻断或转化，以实现对雌蚊的生殖控制，从而控制 吸血和病原体传播。

Abstract: Hematophagous female mosquitoes transmit numerous devastating diseases, while feeding on human blood. A large enough blood-meal is essential for the development of eggs in a female mosquito, thereby interlinking reproduction, blood-feeding and pathogen transmission. Therefore, a clear understanding of the molecular mechanisms regulating egg development can play a critical role in advancement of mosquito control methods. In Aedes aegypti, the Dengue-, Zika- and Yellow fever- transmitting mosquito, two major insect hormones - the juvenile hormone (JH) and the 20-hydroxyecdysone (20E), control the biphasic female mosquito reproductive cycle. The post eclosion (PE) or the pre-vitellogenic maturation phase is under the control of JH, a sesquiterpenoid. Whereas, the post blood meal (PBM) or the vitellogenic phase is mostly controlled by the ecdysteroid, 20E. Some aspects of the molecular basis of JH action has been deciphered in recent times. However, studies on the role of the intermediate factors within the JH/Met regulatory cascade, are ongoing. Gene activation by JH, in most cases, is mediated by direct DNA binding of the JH-receptor Methoprene-tolerant (Met). However, the repression mechanism by JH is indirect, through intermediate factors. This proposal is aimed towards further elucidation of the JH mediated gene activation and repression cascades. Investigation of the role of Krüppel homolog 1(Kr-h1), as a downstream factor of Met in mediating gene repression, and its cooperative action with the long-range repressor Hairy, will be one of the primary foci. The proposed comparative analysis of the chromatin landscapes of JH pathway target genes, should determine the contributions of the components such as Met, Hairy and Kr-h1, on the chromatin states of the target genes. Most studies, on the mechanism of 20E action, have focused on positive gene regulation through the Ecdysone Receptor (EcR). This proposal, is aimed mainly at deciphering the role of 20E and EcR in the previously unexplored area of negative gene regulation, during the vitellogenic period. We plan to elucidate the mechanism of direct and indirect negative regulation and identify co-repressor(s) and intermediate factor(s) of the 20E/EcR-mediated gene repression pathway. This study should potentially lead to identification of targets that can either be blocked or transformed to achieve reproductive control in female mosquitoes, thereby reining blood feeding and pathogen transmission.