ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT

摘要 控制恶性疟原虫红细胞内生长和发育的探讨 发展还处于初级阶段。了解寄生虫的信号和效应物 研究进展将加深我们对这种寄生虫如何在宿主体内生存的了解 并将发现新的化疗靶点。PfHO-1是血红素 红细胞内表达的一种功能未知的加氧酶样蛋白 疟原虫我们已经发现PfHO-1具有卟啉响应DNA- 结合活性，并优先与参与 蛋白质合成我们的假设是PfHO-1对血红素积累有反应 从血红蛋白降解，是至关重要的红细胞内恶性疟原虫 发展本研究的目的就是检验这一假设。我们 将评估PfHO-1对细胞内卟啉扰动的响应 红细胞内恶性疟原虫和E. coli报告系统。我们将 一种新双阳性选择基因敲除对PfHO-1作用的影响 方法和条件表达的卟啉无反应的版本， 蛋白质。这些研究将使我们能够确定PfHO-1是否发挥作用。 在感知细胞卟啉水平和参与关键的 细胞内稳态的各个方面。拟议的实验还将发展 卟啉操作和有害生物选择的新技术 反向基因工程寄生虫的表型。

Abstract Exploration of the control of Plasmodium falciparum intraerythrocytic growth and development is in its infancy. Understanding the signals and effectors of parasite progression will enhance our knowledge of how this parasite survives in its host cell and will uncover new targets for chemotherapy. PfHO-1 is a heme oxygenase-like protein of unknown function expressed in intraerythrocytic malaria parasites. We have found that PfHO-1 has a porphyrin-responsive DNA- binding activity and associates preferentially with genes that are involved in protein synthesis. Our hypothesis is that PfHO-1 responds to heme accumulation from hemoglobin degradation and is crucial for intra-erythrocytic P. falciparum development. The goal of the study proposed here is to test this hypothesis. We will assess the response of PfHO-1 to perturbation of intracellular porphyrin levels in intraerythrocytic P. falciparum and in an E. coli reporter system. We will impair PfHO-1 action by a new double-positive selection gene knockout approach and by conditional expression of a porphyrin-unresponsive version of the protein. These studies will allow us to establish whether PfHO-1 plays an important role in sensing cellular porphyrin levels and participating in critical aspects of cellular homeostasis. The proposed experiments will also develop new technologies for porphyrin manipulation and for selection of deleterious phenotypes in reverse genetically engineered parasites.