ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT

PFHO-1 在恶性疟原虫红细胞内发育中的作用

• 批准号: 8662416
• 负责人: Daniel E. Goldberg
• 金额: $ 17.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662416
• 关键词: Aminolevulinic Acid; Antimalarials; Binding; Cell Nucleus; Cells; ChIP-seq; Chloroquine; Country; DNA; DNA Binding; Development; Disease; Dominant-Negative Mutation; Erythrocytes; Escherichia coli; Food; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic Engineering; Goals; Growth and Development function; Heme; Hemoglobin; Hemopexin; Homeostasis; Human; Knock-out; Knowledge; Malaria; Organism; Oxygenases; Parasites; Peptide Hydrolases; Peptides; Phenotype; Plasmodium falciparum; Play; Porphyrins; Production; Protease Inhibitor; Protein Binding; Protein Biosynthesis; Proteins; Reporter; Ribosomal RNA; Role; Signal Transduction; Source; Supplementation; System; Testing; Time; Transfer RNA; Vacuole; Viral; chemotherapy; heme a; heme biosynthesis; infancy; knockout gene; mutant; new technology; porphyrin a; protoporphyrin IX; public health relevance; research study; response

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.

抽象的 探索控制恶性疟原虫肠内生长的控制和 发展仍处于起步阶段。了解寄生虫的信号和效应子 进步将增强我们对这种寄生虫如何在其宿主中生存的知识 细胞并将发现化疗的新靶标。 PFHO-1是血红素 在肠内表达的未知功能的氧合酶样蛋白 疟疾寄生虫。我们发现PFHO-1具有卟啉响应的DNA- 结合活性并优先与参与的基因相关 蛋白质合成。我们的假设是PFHO-1对血红素的积累做出反应 从血红蛋白降解中，对于肉毒内p.恶性疟原虫至关重要 发展。这里提出的研究的目的是检验这一假设。我们 将评估PFHO-1对细胞内卟啉扰动的响应 肠内恶性疟原虫和大肠杆菌记者系统中的水平。我们将 新的双阳性选择基因敲除损害PFHO-1的动作 方法和条件表达卟啉无反抗的版本 蛋白质。这些研究将使我们能够确定PFHO-1是否扮演 在感测细胞卟啉水平和参与关键的重要作用中 细胞稳态的各个方面。提出的实验也将发展 用于操纵卟啉的新技术和选择有害的技术 反向基因寄生虫反向的表型。