RNA editing is essential to the survival of Trypanosomes and Leishmania, but it does not occur in humans and it is thus being investigated as a target for the development of anti-parasitic drugs. Research in the lab on editing has stimulated discoveries on different types of RNA editing of medical importance by others in the field. 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 processes 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: Trypanosoma.brucei, T.cruzi, and Leishmania species. The lab played a leading role in forming the consortium that sequenced and annotated the genomes of these parasitic pathogens; extended this work through high-throughput proteomic and functional genetic studies; identified and validated many drug targets; and created a consortium to develop drugs for these parasitic diseases. Ongoing studies include collaborations with medicinal chemists who test numerous compounds for their activity against the drug targets and their potential for development into drugs that may move onto clinical trials.
The lab pioneered research on the process of antigenic variation in trypanosomes, which these parasites use to evade elimination by the immune system, thus preventing the development of a vaccine. The lab recently discovered a molecular system that controls the expression of hundreds of surface protein genes in a stage where the parasites only produce one of these at a time. It showed that phosphoinositol metabolites control both the expression of the genes and antigenic switching. Ongoing studies are investigating the mechanisms by which these two processes are controlled; they indicate that complex epigenetic processes including intracellular signaling and molecular interactions within chromosomes are involved.
The lab leads a multi-institutional U19 research program on human immune responses to malaria infection and immunization, that is part of the NIH Human Immunology Project Consortium. Current studies are focused on immune profiling and systems biology approaches in immunology to study the human immune responses to Plasmodium falciparum infection and subunit and attenuated malaria vaccines. Insights gained from this research will have potential for impacting strategies for vaccine development and for treating immune-related diseases more broadly.