REVERSIBLE PROTEIN PHOSPHORYLATION IN APICOMPLEXANS

这一建议的长期目标是参照Apicomplexan寄生虫组中的生化和遗传调节来表征可逆的蛋白质磷酸化途径。原始复合体寄生虫的例子是致命的病原体，如导致疟疾的疟原虫，以及导致艾滋病患者机会性感染的弓形虫和隐孢子虫。仅通过蚊子传播的疟疾就导致全球150万至250万人死亡，其中大部分是幼儿。抗药性寄生虫以及抗药性蚊子的卷土重来，以及疾病的全球传播，迫切需要了解寄生虫的基本调控途径。虽然我们在这一领域的知识仍然很初级，但过去20年积累的大量证据表明，在高等动物中，可逆的蛋白质磷酸化提供了生化和遗传调节的主要机制。因此，在这项提案中，将结合生物化学和分子生物学来研究选定的疟原虫蛋白磷酸酶，这是负责特定磷蛋白去磷酸化的关键酶。这些酶的性质和调节以及它们与特定的生理抑制剂和药物的相互作用将被深入研究。抗寄生虫药物，如有效的海洋毒素冈田酸和免疫抑制剂环孢菌素，将被用作分析寄生虫特定蛋白磷酸酶的结构和功能的工具。这些结果应该成为详细阐明调控途径和可能的药物-靶标相互作用的基石，特别是在疟原虫，以及一般的顶体复合体中。

The long-term goal of this proposal is to characterize the reversible protein phosphorylation pathways in reference to biochemical and genetic regulation in the Apicomplexan group of parasites. Protozan Apicomplexan parasites are exemplified by deadly pathogens such as Plasmodium that causes malaria, and Toxoplasma and Cryptosporidium that cause opportunistic infections in AIDS patients. Malaria, transmitted by mosquitoes, alone kills between 1.5 and 2.5 million people worldwide, mostly young children. The resurgence of drug-resistant parasites as well as pesticide-resistant mosquitoes and the global transmission of the disease have produced an urgent need to understand the fundamental regulatory pathways of the parasite. Although our knowledge in this area is still rudimentary, a large body of evidence accumulated over the last two decades has shown that in higher animals a reversible protein phosphorylation provides a major mechanism of biochemical and genetic regulation. In this proposal, therefore, a combination of biochemistry and molecular biology will be employed to study selected Plasmodium protein phosphatases, key enzymes that are responsible for the dephosphorylation of specific phosphoproteins. The properties and regulation of these enzymes and their interactions with specific physiological inhibitors and drugs will be studied in- depth. The anti-parasitic drugs such as okadaic acid, a potent marine toxin, and cyclosporin, an immunosuppressant, will be used as tools in the analysis of the structure and function of specific protein phosphatases of the parasite. These results should form the cornerstone in the detailed elucidation of the regulatory pathways and possible drug-target interactions in Plasmodium in particular, and Apicomplexans in general.