Malaria remains a major public health threat with more than 225 million people infected worldwide and one fourth of the world's population is at risk for infection. More than a million children die from malaria each year, most of them in Africa. Drug resistance in the parasite is now widespread further compromising prevention and treatment strategies. Much of our previous and ongoing work focuses on understanding the mechanisms of drug resistance in Plasmodium falciparum, the major human malaria parasite. Our goal is to use this knowledge to develop new strategies for drug development and treatment. The mechanisms of drug resistance in the Plasmodium falciparum share many features with drug resistance mechanisms in other systems including many cancers and bacterial systems and thus training in this research area will also prepare a student for work on drug resistance in other systems. Our work has focused on the role of ABC-transporters in mediating drug resistance in malaria and this work has led to a new model for transporter mediated resistance in which subcellular localization of the transporter plays a major role in determining resistance.

Recently, we have expanded our focus to include new drug target discovery using approaches of genomics and functional genomics. We have begun work on the molecular mechanisms of virulence using the methods of whole genome expression analysis. The recent availability of complete genome sequences and methodologies to scan whole genomes now gives an opportunity to investigate such interactions at the molecular level in the relevant human parasite, Plasmodium falciparum. The overall goal of these experiments will be to determine both the number and identity of genes expressed by the human malaria parasite, Plasmodium falciparum in response to drug treatment and to evaluate the role of these genes in for parasite survival. This study makes use of the rapidly expanding database of Plasmodium falciparum sequences being produced by the Malaria Genome Sequencing Project and will focus not only on the individual genes expressed but also on their temporal and quantitative relationship to one another. There will be training opportunities in each of these projects.

Drug resistance is emerging as a major problem in Senegal and training in identifying and tracking new emergent populations is urgently needed. With the tools provided by the malaria genome project and the methods being developed under a newly NIH-funded program it is now possible to study population diversity, and analyze parasite populations from Senegal. The first goal of the initiative would determine the level of parasite diversity. The second goal is to examine the expression profiles of specific parasite genes and the potential modulatory effects of the host immunological status. A third goal will be to examine the role of drug resistance and drug pressure on parasite populations in Senegal.