Creation of a new generation of transgenic mosquitoes to control infectious disease

 描述（申请人提供）：世界上最具破坏性的传染病是虫媒疾病，疟疾和登革热。世界上一半的人口生活在这些疾病的危险地区。根据世界卫生组织和疾病预防控制中心的数据，去年有10亿人感染了疟疾或登革热。尽管大力控制传播疟疾和登革热的蚊子，但它们仍然是巨大的健康问题。这些疾病影响到100多个国家，每年造成100多万人死亡。登革热尤其令人关切，因为其发病率在过去50年中增加了10倍。现在，登革热黄病毒每年感染超过5亿人。显然，目前控制疟疾，特别是登革热的方法是不够的。处理登革热传播的最新方法是释放携带显性突变的转基因雄性蚊子，这些突变在交配时使土著雌性不育或无法繁殖黄病毒。然而，这些释放策略成功的第一个障碍是转基因雄性不能与本地雄性充分竞争，极大地限制了这种有前途的方法的可行性。我们在果蝇的三种信号蛋白中发现了突变，这些突变极大地增加了雄性的性欲，这使得雄性果蝇在交配中击败了野生型雄性果蝇。由于苍蝇和蚊子都是双翅目，我们在苍蝇中发现的基因在蚊子中是保守的，我们建议这些发现将使我们能够在蚊子中推出一种革命性的新方法，旨在增加转基因登革热蚊子-伊蚊的性欲。我们建议在三个相应的伊蚊基因中创造突变，我们认为这将大大增加这些蚊子在竞争中击败土著男性的适应性。作为该模型的第一个测试，我们将在实验室笼中与野生型雄性进行竞争测试，然后在室外野外围栏中进行野外笼研究。我们

 DESCRIPTION (provided by applicant): The most devastating infectious diseases worldwide are the insect-borne diseases, malaria and Dengue fever. Half the world's population lives in areas at risk for these diseases. According to WHO and the CDC, one billion people came down with malaria or Dengue last year. Despite intensive efforts to control the mosquitoes that spread malaria and Dengue, they remain enormous health problems. These diseases affect >100 countries, and kill >1,000,000 people each year. Dengue is of particular concern, as its incidence has increased 10-fold over the last 50 years. Now, the Dengue flavivirus infects upwards of 500,000,000 people annually. Clearly, current approaches to control malaria and, especially Dengue, have been inadequate. The latest approach to dealing with the spread of Dengue, is to release transgenic male mosquitoes bearing dominant mutations that, upon mating, render indigenous females either sterile or unable to reproduce the flavivirus. However, the #1 obstacle to the success of these release strategies is that the transgenic males do not compete adequately with native males, greatly limiting the feasibility of this otherwise promising approach. We discovered mutations in three Drosophila signaling proteins that greatly increase male sex drive, and this allows the male flies to outcompete wild-type males in mating. Since flies and mosquitoes are both Diptera, and the genes we discovered in flies are conserved in mosquitoes, we propose that these findings will allow us to launch a revolutionary new approach in mosquitoes, aimed at increasing the sex drive of transgenic Dengue mosquitoes-Aedes aeypti. We propose to create mutations in the three corresponding Aedes genes, which we posit will greatly increase the fitness of these mosquitoes in outcompeting indigenous males. As a first test of this model, we will perform competition tests with wild-type males in laboratory cages, and then in field cage studies in outdoor field enclosures. We