Discovering new compounds to treat global infectious disease

摘要 世界卫生组织目前的估计表明，全球传染病病例是 正在崛起。疟疾在非洲和南非的贫穷和不发达国家仍然是一种毁灭性的疾病 美洲和亚洲，据报告2009年那里有近100万人死亡。在这些地区，寄生虫可以 迅速产生抗药性，这会侵蚀抗疟疾药物的疗效。因此，新的药物和 迫切需要确定新的目标来治疗疟疾。 我与迈克尔·马莱塔教授(加州大学伯克利分校)的研究生研究涉及到详细的机械研究 对人类健康很重要的酶。了解更多有关传染病和化学物质的知识 我加入了乔恩·克拉迪教授在哈佛医学院的实验室。在HMS，我接受了培训， 处理疟疾寄生虫的血液和肝脏阶段。这次训练让我培养了一种 高通量筛选以确定肝期疟疾的抑制剂。在接下来的两年里，我计划放映 用于治疗疟疾的潜在疗法的几个小分子文库(具体目标1)。在我的 在HMS的时候，我还将与几位专家一起培训，学习如何在疟疾中产生基因敲除， 培养抗药性寄生虫品系，并保持转基因蚊子品系。然后我就可以使用这个培训了 以评估我已确定的肝期疟疾抑制剂靶标的寄生虫的生物学过程 (特定目标2)，并对蛋白质靶标进行生物化学表征(特定目标3)。培训 解决具体目标2和3所需的工作将在HMS的K99阶段完成， 但大多数实验将在颁奖的独立阶段完成。 我计划申请一个终身教职的学术职位，目标是领导一个专注于 描述促进疾病的疟疾寄生虫的基本过程和蛋白质 进程。HMS非常适合建议的K99训练期，因为它拥有最先进的 吞吐量筛查设施，是传染病研究的领先者，其项目包括 哈佛疟疾倡议。我相信在接下来的两年里我所接受的课程和培训将会扩大 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，使 作为一名独立研究员，我非常适合从事全球传染病的工作。

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.