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

 描述(申请人提供)：全球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高危地区。根据世卫组织和疾控中心的数据，去年有10亿人感染了疟疾或登革热。尽管加紧努力控制传播疟疾和登革热的蚊子，但它们仍然存在巨大的健康问题。这些疾病影响100个国家，每年导致100万人死亡。登革热尤其令人担忧，因为其发病率在过去50年中增加了10倍。现在，每年有超过5亿人感染登革热黄病毒。显然，目前控制疟疾，特别是登革热的方法是不够的。应对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，这种突变在交配时会使本土雌性蚊子不育或无法繁殖黄病毒。然而，这些释放策略成功的首要障碍是转基因雄性没有与本地雄性充分竞争，这极大地限制了这种原本有希望的方法的可行性。我们发现了三种果蝇信号蛋白的突变，这些突变极大地提高了雄性果蝇的性欲，这使得雄性果蝇在交配时比野生雄性果蝇更具竞争力。由于苍蝇和蚊子都是双翅目，而我们在苍蝇中发现的基因在蚊子中是保守的，我们认为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-埃及伊蚊的性欲。我们建议在三个相应的伊蚊基因中产生突变，我们认为这将极大地提高这些蚊子在竞争中击败本土雄性蚊子的适合度。作为这个模型的第一个测试，我们将在实验室的笼子里与野生型雄性进行竞争测试，然后在户外的野外围栏中进行野外笼子研究。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