Malaria Parasite Sexual Development and Drug Resistance

疟疾基因组单位使用疟疾寄生虫基因组数据库并开发新的资源，以研究抗药性的机制、寄生虫性发育过程中的基因调控以及寄生虫种群的多样性和进化。在去年取得的进展的基础上，我们现在已经收集了恶性疟原虫所有14条染色体上的基因(~5000)的单核苷酸多态(SNPs)。 我们目前正在努力开发一个平台，使我们能够对大量SNPs进行基因分型。我们还批准了一项IRB方案，用于从柬埔寨的野外地点收集寄生虫。 为了研究染色体单倍型、种群结构和重组率变异，我们对来自世界各地的99个分离株的3号染色体上的183个SNP进行了基因分型。我们发现不同寄生虫种群和3号染色体的重组率差异很大。我们还完成了176株间日疟原虫分离株和其他5种灵长类疟疾物种的线粒体基因组测序。我们的数据支持间日疟原虫的宿主开关假说和亚洲猴间日疟原虫的起源。 我们实验室的另一项主要工作是研究与寄生虫性别分化相关的基因表达和调控。利用基因芯片和基因定位技术，我们已经确定了一个可能在配子体发育中起关键作用的基因。在基因敲除目标基因后，正在评估表型变化。我们目前正在研究该基因的功能。制备了抗配子体的单抗，并正在鉴定抗体识别的靶蛋白。这些抗体在阻断传播方面的潜力也正在测试中。

The Malaria Genomic Unit uses the malaria parasite genome databases and develops new resources to study the mechanism of drug resistance, gene regulation during parasite sexual development, and parasite population diversity and evolution. Building on progress made last year, we have now collected single nucleotide polymorphisms (SNPs) from genes (~5000) on all of the 14 chromosomes of Plasmodium falciparum. We are currently working to develop a platform that will allow us to genotype large number of SNPs. We also have an IRB protocol approved for collecting parasites from field sites in Cambodia. To study chromosomal haplotypes, population structures, and recombination rate variation, we genotyped 183 SNPs on chromosome 3 from 99 worldwide isolates. We found that recombination rate varied greatly among parasite populations and across chromosome 3. We have also finished sequencing the mitochondrial genome from 176 P. vivax isolates and 5 other primate malaria species. Our data support the hypothesis of host switches and origin of P. vivax from Asian monkeys. Another major effort of our laboratory is to study gene expression and regulation associated with the parasite sexual differentiation. We have identified a gene that may play a key role in gametocyte development using microarray and genetic mapping. Phenotypic changes are being evaluated after genetic knockout of the target gene. We are currently studying the function of the gene. Monoclonal antibodies against gametocyte were produced, and the target proteins recognized by the antibodies are being identified. The potential of the antibodies in blocking transmission are also being tested.