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.

摘要