The increasing burden of malaria, in part, due to drug resistance in the parasite Plasmodium falciparum, demands new therapies. Recent research in the field of transcription has demonstrated the functional importance of chromatin in regulating gene expression in eukaryotes. Enzymes that modulate chromatin structures have a profound effect on controlling gene expression. Among these enzymes, histone acetyltransferases (HATs), which transfer the acetyl group from acetyl-CoA to the lysine residues in the N- terminal tails of histones, are the best studied. The antiparasitic effects of drugs that disturb histone acetylation and recent studies from our group on the chromatin remodeling factors in P.falciparum demonstrated that dynamic histone acetylation is an important epigenetic mechanism of transcription regulation and plays a prominent role in development of the malaria parasite. Thus, we propose to 1) characterize two families of transcription-related HAT proteins, 2) determine their functional roles in global transcription regulation, and 3) identify the subunits of multiprotein HAT complexes in P. falciparum. HAT proteins will be characterized using molecular and biochemical approaches, and their functions in parasite development and transcription regulation will be determined by targeted gene disruption and genome-wide expression analysis. This proposed research aims to reveal the epigenetic mechanisms in transcription regulation that controls the parasite development and virulence. The fundamental importance of histone acetylation in gene regulation and the great potential of HAT and histone deacetylase as drug targets underline the significance of research in this area, which may lead to novel antimalarial drugs. Malaria is still a major public health problem in many countries. Its recent resurgence in prevalence is partially due to drug resistance. This study aims to characterize the functions of a group of enzymes that regulate parasite gene expression, which may lead to the design of novel antimalarial drugs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Joy, Deirdre A
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Pennsylvania State University
Schools of Earth Sciences/Natur
University Park
United States
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Gupta, Bhavna; Xu, Shuhui; Wang, Zenglei et al. (2014) Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from north-east Myanmar. J Antimicrob Chemother 69:2110-7
Miao, Jun; Fan, Qi; Parker, Daniel et al. (2013) Puf mediates translation repression of transmission-blocking vaccine candidates in malaria parasites. PLoS Pathog 9:e1003268
Miao, Jun; Wang, Zenglei; Liu, Min et al. (2013) Plasmodium falciparum: generation of pure gametocyte culture by heparin treatment. Exp Parasitol 135:541-5
Miao, Jun; Lawrence, Matthew; Jeffers, Victoria et al. (2013) Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. Mol Microbiol 89:660-75
Childs, Ronnie A; Miao, Jun; Gowda, Channe et al. (2013) An alternative protocol for Plasmodium falciparum culture synchronization and a new method for synchrony confirmation. Malar J 12:386
Liu, Zhenyu; Miao, Jun; Cui, Liwang (2011) Gametocytogenesis in malaria parasite: commitment, development and regulation. Future Microbiol 6:1351-69
Miao, Jun; Cui, Liwang (2011) Rapid isolation of single malaria parasite-infected red blood cells by cell sorting. Nat Protoc 6:140-6
Cui, Liwang; Miao, Jun (2010) Chromatin-mediated epigenetic regulation in the malaria parasite Plasmodium falciparum. Eukaryot Cell 9:1138-49
Miao, Jun; Li, Xiaolian; Cui, Liwang (2010) Cloning of Plasmodium falciparum by single-cell sorting. Exp Parasitol 126:198-202
Miao, Jun; Fan, Qi; Cui, Long et al. (2010) The MYST family histone acetyltransferase regulates gene expression and cell cycle in malaria parasite Plasmodium falciparum. Mol Microbiol 78:883-902

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