College of Veterinary Medicine

 

 

Education:

PhD, Biochemistry, University of Washington, Seattle, 1977
Postdoctoral fellowship, University of North Carolina, Chapel Hill, 1977-1980

Research Interests:

Emerging and re-emerging pathogens of animals and man; Molecular biology of the malaria parasite; Drug target identification in Plasmodium falciparum; Novel diagnostics approaches for emerging diseases.

Current Projects:

Roles of the plasmepsin family of aspartic proteases in the lifecycle of the malaria parasite. The long range goal of this project is to develop a novel class of antimalarial drugs that function by inhibiting the aspartic proteinases of the human malaria parasite. Our hypothesis is that one or more of these enzymes (called plasmepsins) perform(s) (an) essential function(s) in during the lifecycle of the parasite and that potential antimalarial drugs exist among inhibitors of these enzymes. Our studies are focused on identifying the biological functions of the various members of the plasmepsin family using a combination of gene knockout and knockdown approaches. Plasmepsins identified as performing essential functions are prepared as recombinant proteins, characterized by substrate and inhibitor kinetics, followed by structural studies, rational design of novel inhibitors and in vivo screening.

Develop genetic tools for conditional knockout/knockdown mutagenesis in Plasmodium spp. Sustaining our capacity to prevent and treat human malaria is dependent upon developing new, effective antimalarial drugs, since resistance to drugs now in use is widespread, and no effective vaccine is available. New antimalarial drugs may be rationally designed that inhibit the functioning of parasite gene products that perform essential cellular processes. The objective of this study is to develop genetic methods that will positively identify genes performing processes essential for growth of the malaria parasite, thus completing a critical first step toward drug development.

Establish the DNA gyrase of the apicoplast as a therapeutic target in Plasmodium spp. The apicoplast is a unique organelle derived from an ancestral algal chloroplast. The identification of a novel DNA gyrase-like target sensitive to established antimicrobial inhibitors will open potential avenues for the rational development of new antimalarial drugs and provide a valuable tool for investigating the role of these enzymes in the replication and transcription of the 35 kb plastid DNA. Furthermore, since DNA gyrase is likely to exist in all plastid containing apicomplexans and plants, the proposed studies will likely provide important insight into the basic role(s) of this bacterial-like topoisomerase in the regulation of eukaryotic plastid DNA structure and function.

Selected Publications:

For Publications Extracted From Medline Click HERE

Dame, J.B., G.R. Reddy, C.A. Yowell, B.M. Dunn, J. Kay, and C. Berry. 1994. Sequence, Expression and Modeled Structure of An Aspartic Proteinase from the Human Malaria Parasite Plasmodium falciparum. Molecular and Biochemical Parasitology 64:177-190.

Dame, J.B., D.E. Arnot, P.F. Bourke, D. Chakrabarti, Z. Christodoulou, R.L. Coppel, A.F. Cowman, A.G. Craig, K. Fischer, J. Foster, N. Goodman, K. Hinterberg, A.A. Holder, D.C. Holt, D.J. Kemp, M. Lanzer, A. Lim, C.I. Newbold, J.V. Ravetch, G.R. Reddy, J. Rubio, S.M. Schuster, X. Z. Su, J.K. Thompson, F. Vital, T.E. Wellems, and E.B. Werner. 1996. Current status of the Plasmodium falciparum genome project. Molecular and Biochemical Parasitology 79:1-12.

Westling, J., C.A. Yowell, P. Majer, J.W. Erickson, J.B. Dame, and B.M. Dunn. 1997. Plasmodium falciparum, P. vivax, and P. malariae: A comparison of the active site properties of plasmepsins cloned and expressed from three different species of the malaria parasite. Experimental Parasitology 87:185-193.

Jiang, S.P., S.T. Prigge, L. Wei, Y.E. Gao, T.H. Hudson, L. Gerena, J.B. Dame, and D.E. Kyle. 2001. New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. Antimicrobial Agents and Chemotherapy 45:2577-2584.

Dame, J.B., C.A. Yowell, A.L. Omara-Opyene, J.M. Carlton, R.A. Cooper, and T. Li. 2003. Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man. Mol. Biochem. Parasitol. 130:1-12.

Li, T., C.A., Yowell, B.B. Beyer, S.-H. Hung, J. Westling, M.T. Lam, B.M. Dunn, and J.B. Dame. 2004. Recombinant expression and enzymatic subsite characterization of plasmepsin 4 from the four Plasmodium species infecting man. Mol.Biochem.Parasitol. 135: 101-109.

Omara-Opyene A.L., P.A. Moura, C.R. Sulsona, J.A. Bonilla, C.A. Yowell, H. Fujioka, D.A. Fidock, and J.B. Dame. 2004. Genetic disruption of the Plasmodium falciparum digestive vacuole plasmepsins demonstrates their functional redundancy. J. Biol. Chem. 279:54088-54096.

Khor, V., C.A. Yowell, J.B. Dame, T.C. Rowe. 2005. Expression and characterization of the ATP-binding domain of a malarial Plasmodium vivax gene homologous to the B-subunit of the bacterial topoisomerase DNA gyrase. Mol. Biochem. Parasitol. 140:107-117.

Bonilla, J.A., Moura, P.A., Bonilla, T.D., Yowell, C.A., Fidock, D.A., Dame, J.B. 2007. Effects on growth, hemoglobin metabolism and paralogous gene expression resulting from disruption of genes encoding the digestive vacuole plasmepsins of Plasmodium falciparum. Intl. J. Parasitol. 37:317-327.