RNA editing is essential to the survival of Trypanosomes and Leishmania, but it does not occur in humans and thus being investigated as a target for the development of anti-parasitic drugs. Research in the lab on editing stimulated discoveries by others of medical important different types of RNA editing in humans. The lab determined the molecular mechanism of editing, identified and characterized the molecular machinery, showed that it is essential in the disease stage, and validated several of its components as therapeutic targets. Current studies are characterizing the structure and functions of multiple proteins of the editing machinery in detail and the regulation of the process for the purpose of drug development.
The lab is using a cell-wide systems biology approach to elucidate critical cellular processes in trypanosomatid parasites that can be exploited for the development of drugs against three related parasites. The lab played a leading role in forming the consortium that sequenced and annotated the genomes of three major parasitic pathogens, extended this through high-throughput proteomic and functional genetic studies, the identification and validation of many drug targets, and the creation of a consortium to develop drugs for these parasitic diseases. Ongoing studies include collaborations with medicinal chemists and testing numerous compounds for their activity against the drug targets and potential for development into drugs that can move to clinical trials.
The lab pioneered research on the process of antigenic variation in trypanosomes by which these parasites evade elimination by the immune system, which prevents the development of a vaccine. Recent discoveries in the lab have uncovered the cellular system that controls the antigenic variation. The lab discovered that specific glycolipids control both that only one of thousands of surface protein genes is active at a time and the switching between which of the genes is active. Ongoing studies are investigating the mechanism by which these two processes are controlled but already indicate that they are by complex epigenetic processes that involve cellular signaling systems and chromosome molecular interactions.
The lab is conducting research on malaria. It characterized the parasite’s protein complex that both metabolizes host erythrocyte hemoglobin and detoxifies the released heme. The lab also leads a multi-institutional program that is studying the human immune response to malaria infection and experimental vaccination. Current studies are focused on performing systems immunology analysis of human immune responses to subunit and attenuated malaria vaccines. These studies are being also integrated within the NIH Human Immunology Project Consortium.