• Primary Faculty Profiles
• Bankert, Richard, Ph.D., V.M.D., Professor
• Bianco, Piero, Ph.D., Associate Professor
• Campagnari, Anthony, Ph.D., Professor
• Collins, Arlene, Ph.D., Associate Professor
• Connell, Terry, Ph.D., Professor
• Egilmez, Nejat, Ph.D., Associate Professor
• Hakansson, Anders, Ph.D., Assistant Professor
• Hay, John, Ph.D., Professor
• Jacobs, Amy, Ph.D., Assistant Professor
• Melendy, Thomas, Ph.D., Associate Professor
• Panepinto, John, Ph.D., Assistant Professor
• Read, Laurie, Ph.D., Professor
• Russell, Michael, Ph.D., Professor
• Ruyechan, William, Ph.D., Professor and Chairman
• Thacore, Harshad, Ph.D., Associate Professor
• Williams, Noreen, Ph.D., Professor
• Adjunct Faculty Profiles
• Departmental Publications
• Career Opportunities
• The Witebsky Center
• Seminars

Faculty and Research

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Education:

1984 - 1987, Postdoc, Johns Hopkins University, Baltimore, MD
1981 - 1984, Postdoc, Johns Hopkins Sch. Med. Baltimore, MD
1981, Ph.D., New York University
1977, Bachelor of Science, University of Maine, Orono, Maine

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Research Interests:

Developmental Regulation of Gene Expression in Trypanosomes
Our laboratory uses molecular biological and biochemical approaches to study a group of parasitic protozoans that cause disease in humans and domestic animals in much of the tropical world.  Two projects focus on Trypanosoma brucei, the causative agent of African sleeping sickness, which is transmitted by the tse-tse fly. A third project focuses on Trypanosoma  cruzi, which causes Chagas' disease in South and Central America and is transmitted by the reduviid bug. Treatment for these diseases is severely limited due to increasing drug resistance and issues of drug toxicity or lack of available drugs. The goal of our work is to discover and exploit regulatory events that occur in the parasite life cycle that may be used to prevent growth or transmission of the parasite.

The first project centers on the mitochondrial ATP synthase of T. brucei. This protein complex couples the energy generated by the electron transport chain to the synthesis of ATP. In T. brucei we have shown that the ATP synthase is regulated through the life cycle of the organism by several unique mechanisms which appear to be different from the regulatory mechanisms for other mitochondrial proteins such as those in the electron transport chain. This regulation may be critical to understanding how this parasite responds to change in the environment due to the two host organisms (in this case, the tsetse fly and the cow). We have shown a differential regulation for the component subunits of this complex at the level of mRNA stability and are now examining the specific sequences and nucleic acid binding proteins involved in this regulation. We have also used RNA interference to create genetic knock downs as a tool to understanding the role of the ATP synthase in the parasites survival in its hosts. Our recent data shows that the ATP synthase is responsible for maintaining a mitochondrial membrane potential in the bloodstream stage of the parasite. This membrane potential is required for the parasite's survival since without it the parasite cannot pre-adapt for survival in the insect vector. These results suggest that the ATP synthase may provide an excellent target for drug development focused on preventing transmission of the parasite by the insect.

The second project, examines a pair of unique RNA binding proteins, P34 and P37, which are highly homologous to one another. We have shown that these proteins interact with 5 S rRNA and hypothesize that they act to chaperone the 5 S rRNA from the nucleus where it is synthesized by RNA polymerase III, to the nucleolus for assembly with other ribosomal components. More recently we have shown that these proteins are essential for proper ribosomal biogenesis and the survival of the parasite. The role of these trypanosome-specific proteins in a normally highly conserved pathway of ribosomal biogenesis is a surprising finding and may suggest that these proteins could be developed as targets for chemotherapy.

In addition, we have studied these proteins as models for mechanisms of developmental regulation in trypanosomes. Expression of the smaller of the two proteins, P34, is regulated by differential mRNA stability and we have identified AU rich elements present in the 3' untranslated region of this transcript that are responsible. In constrast, expression of the larger protein, p37, is regulated translationally, possibly by sequences in the 3' untranslated region as well. Most interestingly, the regulation of the two proteins are exactly opposite one another making them an excellent target to examine developmentally regulated genes.

In the third project in collaboration with Dr. Beatriz Garat at the Universidad de la Républica in Uruguay, we are examining proteins which bind to dinucleotide repeats occurring in the intergenic regions of the genome of Trypanosoma cruzi. This project, which has been funded by the Fogarty Foundation, examines whether these repeats together with their cognate binding proteins may be involved in gene regulation in T. cruzi.

Relevant references:

Brown, S.V., Hosking, P., Li, J.L., and Williams, N. (2006) The Mitochondrial ATP Synthase is responsible for maintenance of membrane potential in bloodstream T. brucei. Euk. Cell 5: 45-53.

Pérez-Díaz, L., Duhagon , M., Smircich, P., Sotelo-Silveira, J., Robello, C. , Krieger, M.,   Goldenberg, S., Williams, N., Dallagiovanna, B. and Garat, B. (2007) Trypanosoma cruzi: Molecular characterization of an RNA binding protein differentially expressed in the parasite life cycle. Exp. Parasitol. 117: 99-105.

Hellman, K., Ciganda, M., Brown, S.V., Li, J.L., Ruyechan, W.T., and Williams N (2007) Two trypanosome-specific proteins are essential factors for 5S rRNA abundance and ribosomal assembly in T. brucei Euk. Cell 6: 1766-17772.

Hellman, K., Prohaska, K., and Williams, N. (2007) T.  brucei RNA binding proteins, p34 and p37, mediate NOPP44/46 localization via the exportin 1 pathway.  Euk. Cell 6: 2206-2213.

Prohaska, K. and Williams, N. (2008) Assembly of the Trypanosoma brucei 60S ribosomal subunit nuclear export complex requires trypanosome-specific proteins P34 and P37 (in press, Euk. Cell)