Novel antimalarial strategies using metabolomic network discovery

疟疾是影响5亿多人的一个重大全球健康问题， 每年导致3-5百万人死亡。这种疾病是由寄生虫属 恶性疟原虫是最致命的种类。宿主-病原体 疟原虫和宿主红细胞之间的关系是所有 疟疾疾病的临床表现，是一个连续的48小时周期， 在实验室中被忠实地复制。尽管对疟疾的研究已经进行了世纪， 它仍然是一个主要的健康问题，主要是因为抗药性寄生虫 的崛起，规避长期有效的药物治疗。因此，有一个更新的 迫切需要找到新的化疗药物来治疗这种疾病。 该提案旨在提供第一个全球性的代谢分析， 恶性疟原虫的宿主-病原体相互作用， 确定新的药物靶点。任何病原体编码的代谢途径 基因组定义了它可以自主调节的化学过程的全部内容。 所有其他代谢物必须从宿主细胞中摄取或从前体代谢 通过主机提供。因此，宿主细胞和病原体是密切相关的 通过病原体对宿主的营养依赖P. 恶性疟原虫表明这种生物体在生物化学上是独特的：其基因组的60% 编码生物学上从未见过的蛋白质，剩下的40%包含很少的 在几乎所有其他真核生物中发现的基本代谢基因。这表明 疟原虫和宿主红细胞之间的相互作用机制可能 揭示了新的代谢酶，可以为药理学提供新的靶点， 干预使用最近开发的质谱技术，我们将 定量疟原虫感染细胞中的代谢物，并整合这些数据和其他数据 生成网络交互模型，揭示了这种致命的生物学见解， 病原体

Malaria is a major global health issue affecting over half a billion people and resulting in 3-5 million deaths annually. This disease is caused by parasites of the genus Plasmodium with P. falciparum being the most lethal species. The host-pathogen relationship between Plasmodium and the host red blood cell is responsible for all clinical manifestations of the malaria disease and is a continuous 48-hour cycle that can be faithfully reproduced in the laboratory. Despite over a century of research on malaria, it continues to be a major health problem largely because drug-resistant parasites are on the rise, circumventing long-efficacious drug treatments. Thus, there is a renewed urgency to identify novel chemotherapeutics to treat this disease. This proposal aims to provide the first global analysis of the metabolic host-pathogen interactions for Plasmodium falciparum as a means to identify novel drug targets. The metabolic pathways encoded in any pathogen genome define the repertoire of chemical processes that it can autonomously regulate. All other metabolites must be taken up from the host cell or metabolized from precursors available through the host. Therefore, the host cell and pathogen are intimately linked through the reliance of the pathogen on the host for nutrients. The genome of P. falciparum suggests that this organism is biochemically unique: 60% of its genome encodes proteins never seen before in biology, and the remaining 40% contains very few of the fundamental metabolic genes found in almost all other eukaryotes. This indicates that the mechanism of interaction between Plasmodium and the host red blood cell may reveal novel metabolic enzymes that can provide new targets for pharmacological intervention. Using recently developed mass spectrometry techniques, we will quantitate metabolites in Plasmodium-infected cells and integrate these and other data to generate network interaction models revealing new biological insights into this deadly pathogen.