Discovering new compounds to treat global infectious disease

描述（由申请人提供）：世界卫生组织目前的估计表明，全球传染病病例正在上升。在非洲、南美洲和亚洲的贫穷和不发达国家，疟疾仍然是一种破坏性疾病，据报告，2009年这些国家有近100万人死亡。在这些地区，寄生虫可迅速产生耐药性，从而削弱抗疟药的效力。因此，迫切需要新的药物和新的靶点来治疗疟疾。我的研究生课程师从加州大学伯克利分校的Michael Marletta教授，涉及对人类健康至关重要的酶的详细机制研究。为了更多地了解传染病和化学生物学，我加入了哈佛医学院（HMS） Jon Clardy教授的实验室。在英国皇家医学学院，我接受了疟疾寄生虫血液和肝脏阶段的培训。这次培训使我能够开发出一种高通量筛选方法来识别肝期疟疾的抑制剂。在接下来的两年里，我计划筛选几个潜在的治疗疟疾的小分子文库（Specific Aim 1）。在HMS期间，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，培养耐药的寄生虫菌株，以及维持转基因蚊子系。然后，我可以利用这种培训来评估寄生虫的生物过程，我确定的肝期疟疾抑制剂的目标（Specific Aim 2），并进行生化表征

DESCRIPTION (provided by applicant): 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-throughput screen to identify inhibitors of liver stage malaria. In the next two years I plan o 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.