Discovering new compounds to treat global infectious disease

摘要 世界卫生组织目前的估计表明， 升中国疟疾仍然是非洲、南非洲和非洲贫穷和不发达国家的一种毁灭性疾病。 美洲和亚洲，2009年报告的死亡人数接近100万。在这些地区，寄生虫可以 疟疾患者迅速产生耐药性，从而削弱抗疟药物的效力。因此，新药和 迫切需要鉴定新的靶点来治疗疟疾。 我在Michael Marletta教授（加州大学伯克利分校）的研究生学习涉及详细的机械研究， 对人体健康很重要的酶。了解更多关于传染病和化学 我加入了哈佛医学院乔恩·克拉迪教授的实验室。在HMS，我接受了培训， 对血液和肝脏阶段的疟疾寄生虫都有效。这次培训使我能够开发一个 高通量筛选以鉴定肝期疟疾抑制剂。在接下来的两年里，我计划筛选 用于治疗疟疾的潜在疗法的几个小分子文库（具体目标1）。在我 在HMS期间，我还将与几位专家一起学习如何在疟疾中产生基因敲除， 培养抗药性寄生虫品系，维持转基因蚊子品系。然后我就可以用这个训练 来评估我发现的肝期疟疾抑制剂所针对的寄生虫的生物学过程 （具体目标2）和生物化学表征蛋白质靶标（具体目标3）。培训 解决具体目标2和3所需的工作将在合同的K99阶段在HMS完成， 但大部分实验将在独立阶段完成。 我计划申请一个终身制的学术职位，目标是领导一个研究小组， 描述了疟疾寄生虫促进疾病的基本过程和蛋白质 过程HMS非常适合拟议的K99训练期，因为它具有最先进的高性能， 通量筛选设施，是传染病研究的领导者， 哈佛疟疾倡议。我相信我在未来两年所接受的课程和培训将会拓宽 我对寄生虫生物学的理解，很好地补充了我以前在酶学方面的技能， 我非常适合作为一名独立研究人员从事全球传染病研究。

Abstract Current estimates from the World Health Organization suggest that global cases of infectious disease are rising. Malaria remains a devastating disease in poor and undeveloped countries in Africa, South America and Asia, where nearly one million deaths were reported in 2009. In these areas, parasites can rapidly develop drug resistance, which erodes the efficacy of antimalarials. Thus new drugs and the identification of novel targets are desperately needed to treat malaria. My graduate studies with Prof. Michael Marletta (UC Berkeley) involved detailed mechanistic studies on enzymes that are important to human health. To learn more about infectious disease and chemical biology I joined Prof. Jon Clardy's lab at Harvard Medical School (HMS). At HMS I received training to work with both the blood and liver stages of the malaria parasite. This training allowed me to develop a high-throughout screen to identify inhibitors of liver stage malaria. In the next two years I plan to screen several small molecule libraries for potential therapeutics to treat malaria (Specific Aim 1). During my time at HMS I will also train with several experts to learn how to generate genetic knockouts in malaria, raise drug resistant parasite strains, and maintain transgenic mosquito lines. I can then use this training to evaluate the biological processes of the parasite that my identified liver stage malaria inhibitors target (Specific Aim 2) and to biochemically characterize the protein targets (Specific Aim 3). The training needed to address Specific Aims 2 and 3 will be completed at HMS during the K99 phase of the award, but most of the experiments will be completed during the independent phase of the award. I plan to apply for a tenure-track academic position with the goal of leading a research group focused on characterizing essential processes and proteins of the malaria parasite that facilitate the disease process. HMS is ideally suited for the proposed K99 training period as it has a state-of-the-art high- throughput screening facility and is a leader in infectious disease research with programs like the Harvard Malaria Initiative. I believe the courses and training I receive in the next two years will broaden my understanding of parasite biology and nicely complement my previous skills in enzymology to make me uniquely suited to work on global infectious disease as an independent researcher.