Malaria, the world's most important parasitic disease, is caused by intraerythrocytic protozoan parasites of the genus Plasmodium. Four species of Plasmodium are infectious to humans: Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax. They annually cause clinical illness in 300 to 500 million people with 1.5 to 2.7 million deaths, mainly caused by P. falciparum. The life cycle of Plasmodium species is spent between two hosts, Anopheles mosquitoes in which the parasite undergoes one sexual and multiple rounds of asexual divisions, and a vertebrate host in which the parasite multiplies asexually. This life cycle involves various morphogenetic states each equipped with the structural and regulatory components and the metabolic machineries needed to proliferate and advance into the next developmental stage. For each of the parasite's life stages, the genome is transcribed in a very precise manner. Classic microarray studies of the intraerythrocytic life cycle have defined an ordered process or """"""""just in time"""""""" pattern of transcription. Despite this knowledge of the pattern of transcription, very little is known regardig the protein factors that regulate the transcription process. Genome analysis has indicated that there is a dearth of classically defined or evolutionarily conserved transcription factors present. Additionally, little is known in Plasmodium of how potential transcription factors are linked to th basal transcriptional machinery, found in all eukaryotic cells. We have begun an analysis of an evolutionarily conserved factor (P. falciparum Multiprotein Bridging Factor 1 [PfMBF1]) that may provide a crucial link between gene-specific transcription factors and the basal machinery, including the TATA binding factor (TBP). The major goal of this application is to elucidate the role of PfMBF1 and define the nature of the protein complex involving PfMBF1 and other components of the transcriptional machinery. Specifically, we will determine whether PfMBF1 occupies the promoter region of certain expressed genes and investigate the potential interaction with a rhoptry-specific AP2 transcription factor. Preliminary evidence suggests that PfMBF1 is essential for parasite viability and we will use state-of-the art genetic approaches to investigate the role of this protein. Finally, we will determine the molecular composition of the transcriptional complex containing PfMBF1. This information will add in the determining the key role of this molecule and may point out steps of potential chemotherapeutic intervention.

Public Health Relevance

Malaria, the world's most important parasitic disease, is caused by intraerythrocytic protozoan parasites of the genus Plasmodium. At present, there is no effective vaccine and the incidence of drug resistant parasites and treatment failures is increasing significantly around the world. New insights in the biology of the organism and the biochemical mechanisms responsible for key processes may identify new potential targets for drug or vaccine development. The process of transcription in Plasmodium has many unique aspects as compared to its host organisms and thus may allow intervention at these key processes. Additional the proposed studies may provide a valuable genetic resource to the malaria community.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-M (02))
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Mcgugan, Glen C
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Drexel University
Schools of Medicine
United States
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