Identification and disruption of mosquito heme transporters

描述（由申请方提供）：埃及伊蚊是登革热、黄热病和基孔肯雅病毒的主要媒介，是研究其他媒介虫媒病毒蚊子的模型系统。对于蚊子来说，获取血粉本质上是一种高风险、高回报的活动--几乎是无限的资源来促进产卵，加上极高水平的铁，必须解毒以防止自由基的产生， 氧化损伤与此相反，血液来源的铁既是鸡蛋生产和发育的必需微量营养素，也是启动卵黄发生过程的关键信号分子。因此，通过高度结构化的铁进口、出口和储存系统，在铁过量和铁缺乏之间存在着良好的平衡。在这项提议中，我们的目标是通过结合高通量测序（aim 1）和靶向基因编辑（aim 2）技术，鉴定和破坏参与分子铁和血红素细胞摄取的蚊子转运蛋白。蚊子铁输入蛋白的鉴定将为旨在破坏蚊子媒介能力的疫苗、药物或转基因策略提供独特的靶标，因为存在于消化道内腔表面上的关键输入者/输出者将暴露于潜在的化学抑制剂或中和抗体（如果存在于血粉中）。

DESCRIPTION (provided by applicant): Aedes aegypti is the main vector of dengue, yellow fever and chikungunya viruses, and is a model system for studies of other mosquitoes that vector arboviruses. The acquisition of a bloodmeal is by nature a high-risk, high reward activity for the mosquito- virtually unlimited resources to fuel egg production, combined with extraordinarily high levels of iron which must be detoxified to prevent free-radical production and oxidative damage. In contrast, blood-derived iron is both an essential micronutrient for egg production and development as well as a critical signaling molecule to initiate the vitellogenic process. Thus, a fine balance exists between iron overload and iron deficiency, achieved through a highly structured system of iron import, export and storage. In this proposal, we aim to identify and disrupt mosquito transport proteins involved in the cellular uptake of both molecular iron and heme using a combination of high-throughput sequencing (aim 1) and targeted gene editing (aim 2) technologies. The identification of mosquito iron import proteins would provide unique targets for vaccine, drug, or transgenic strategies aimed at disrupting mosquito vectorial capacity, as critical importers/exporters present on the lumenal surface of the digestive tract would be exposed to potential chemical inhibitors or neutralizing antibodies if present in the bloodmeal.