Plasmodium falciparum, the causative agent of human malaria, undergoes distinct morphological changes during the progression through its life cycle in the mosquito and human hosts. During the intraerythrocytic life cycle, the parasite diverges from the paradigm of eukaryotic cell cycle by undergoing multiple rounds of DNA replication and forms 8 to 32 merozoites from a single cell. A clear understanding of the biochemical changes and molecular switches that regulate the unusual erythrocytic developmental stages of the malaria parasite has not been established. The long-term goal of this research is to develop a model for cell cycle regulation in the intraerythrocytic stages of development of malaria parasite P. falciparum. The regulation of the precise timing of initiation of DNA synthesis and the relationship between S phase and mitosis during development in P. falciparum remains unclear, as does the identity of the proteins involved in cell cycle progression and how the are regulated. Recent research done in our laboratory has identified a few molecular tools to initiate an in-depth study of the cell cycle regulation of P. falciparum. Specifically, we propose to carry out the following: (a) To identify and characterize components of P. falciparum pre-replication complex, we will initially focus on cell cycle regulated changes in expression, intracellular localization, and phosphorylation of P. falciparum homologues of MCM4, ORC1 and ORC5. (b) Identify proteins interacting with P. falciparum CDK-like kinases, CDK- activating kinases and pre-replication complex components by phage- based interaction cloning, phosphorylation screen of a lambda screen library, and by two-hybrid screen. (c) Develop more effective means of cell cycle synchronization of the parasites. A detailed analysis of P. falciparum cell cycle regulators provide insight into the molecular mechanism of unusual asexual division during Plasmodium schizogony. Furthermore, enzymes involved in cell cycle progression have the potential to be attractive targets for drug development, especially given that differences between cell cycle regulation in parasite and host might permit a level of specificity in directing therapies against the parasite.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048036-04
Application #
6632420
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
2000-06-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$249,375
Indirect Cost
Name
University of Central Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
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Dorin, Dominique; Semblat, Jean-Philippe; Poullet, Patrick et al. (2005) PfPK7, an atypical MEK-related protein kinase, reflects the absence of classical three-component MAPK pathways in the human malaria parasite Plasmodium falciparum. Mol Microbiol 55:184-96
Dobson, Sean; Kumar, Rajinder; Bracchi-Ricard, Valerie et al. (2003) Characterization of a unique aspartate-rich protein of the SET/TAF-family in the human malaria parasite, Plasmodium falciparum, which inhibits protein phosphatase 2A. Mol Biochem Parasitol 126:239-50
Merckx, Anais; Le Roch, Karine; Nivez, Marie-Paule et al. (2003) Identification and initial characterization of three novel cyclin-related proteins of the human malaria parasite Plasmodium falciparum. J Biol Chem 278:39839-50
Doerig, Christian; Endicott, Jane; Chakrabarti, Debopam (2002) Cyclin-dependent kinase homologues of Plasmodium falciparum. Int J Parasitol 32:1575-85
Patterson, Shelley; Whittle, Christina; Robert, Claudia et al. (2002) Molecular characterization and expression of an alternate proliferating cell nuclear antigen homologue, PfPCNA2, in Plasmodium falciparum. Biochem Biophys Res Commun 298:371-6
Dobson, S; Bracchi, V; Chakrabarti, D et al. (2001) Characterization of a novel serine/threonine protein phosphatase (PfPPJ) from the malaria parasite, Plasmodium falciparum. Mol Biochem Parasitol 115:29-39