The Docampo Laboratory has a long-term interest in the chemotherapy of parasitic diseases. Early work on free radical metabolism led to the findings that antifungal azoles are effective agents against Trypanosoma cruzi, and that the mode of action and toxicity of the nitro compounds currently used against these parasites involved free radical intermediates. The lab interest shifted in the early 1990's to the study of calcium homeostasis in parasitic protists. These studies led to the discovery of the acidocalcisomes, acidic organelles rich in calcium and phosphorus that are conserved from bacteria to man (see figure) (http://news.bbc.co.uk/2/hi/science/nature/3003946.stm). For the last few years, the lab has focused on the functions of these organelles in a variety of cells, including trypanosomatids, malaria parasites, Chlamydomonas, Dictyostelium, bacteria, human platelets, and insect, chicken, and sea urchin eggs.
The Docampo lab also found that acidocalcisomes are rich in pyrophosphate and short- and long-chain polyphosphate and that polyphosphate has a variety of novel functions in eukaryotes, from an osmoregulatory function in trypanosomes to a potent procoagulant and antifibrinolytic action in human blood (http://pubs.acs.org/cen/news/84/i03/8403notw9.html). The discovery of high levels of pyrophosphate in the acidocalcisomes also led to the use of pyrophosphate analogs, currently used in the treatment of osteoporosis and other bone diseases (bisphosphonates), as potential chemotherapeutic agents against parasitic protists. Some of these bisphosphonates have been shown to produce radical cures in animal models of leishmaniasis (http://newsarchive.asm.org/aug00/topic1.asp)
More recently, the Docampo lab has investigated the role of another organelle, the contractile vacuole complex, in osmoregulation in trypanosomes. These studies can reveal targets for trypanocidal drugs and have a variety of therapeutic implications. The lab strategy is to search for metabolic pathways in parasites that may be essential for their survival but may not find an equivalent counterpart in the host. Thus, one could look for specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts.
Metabolic pathways of trypanosomatids and malaria parasites
Lander, N., Li, Z.H., Niyogi, S., and Docampo, R. (2015) CRISPR/Cas9-induced disruption of paraflagellar rod proteins 1 and 2 genes in Trypanosoma cruzi reveals their role in flagellar attachment. mBio 6 (4), e01012-15.
Niyogi, S., Jimenez, V., Girard-Dias, W., de Souza, W., Miranda, K., and Docampo, R. (2015) Rab32 is essential for maintaining functional acidocalcisomes and for growth and infectivity of Trypanosoma cruzi. J. Cell Sci. 128, 2363-2373.
Huang, G., Ulrich, P.N., Storey, M., Johnson, D., Tischer, J., Tovar, J.A., Moreno, S.N., Orlando, R. and Docampo, R. (2014) Proteomic analysis of the acidocalcisome, an organelle conserved from bacteria to human cells. PLoS Path. 10 (12): e1004555.
Niyogi, S., Mucci, J., Campetella, O., and Docampo, R. (2014) Rab11 regulates trafficking of trans-sialidase to the plasma membrane through the contractile vacuole complex of Trypanosoma cruzi. PLoS Pathog. 10 (6): e1004224.
Huang, G., Bartlett, P.J., Thomas, A.P., Moreno, S.N.J., and Docampo, R. (2013) Acidocalcisomes of Trypanosoma brucei have an inositol 1,4,5-trisphosphate receptor that is required for growth and infectivity. Proc. Natl. Acad. Sci. USA 110, 1887-1892.
Huang, G., Vercesi, A.E., and Docampo, R. (2013) Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter. Nature Commun. 4, 2865.
Jimenez, V., and Docampo, R. (2012) Molecular and electrophysiological characterization of a novel cation channel ofTrypanosoma cruzi. PLoS Path. 8 (6) e1002750.
Li, Z.H., Alvarez, V.E., De Gaudenzi, J.G., Sant’anna, C., Frasch, A.C., Cazzulo, J.J., Docampo, R. (2011) Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi. J. Biol. Chem. 286, 43959-43971.
Patel, S., and Docampo, R. (2010) Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling. Trends Cell Biol. 20, 277-286.
Patel, S., and Docampo, R. (2009) In with the TRP channels: intracellular functions for TRPM1 and TRPM2. Sci. Signal. 2 (95):pe69.
Smith, S.A., Mutch, N.J., Baskar, D., Rohloff, P., Docampo, R., and Morrissey, J.H. (2006) Polyphosphate modulates blood coagulation and fibrinolysis. Proc. Natl. Acad. Sci. U.S.A., 103, 903-908.
Docampo, R., de Souza, W., Miranda, K., Rohloff, P., and Moreno, S.N.J. (2005) Acidocalcisomes- conserved from bacteria to man. Nat. Rev. Microbiol. 3, 251-261.