A few years ago we discovered a novel organelle in trypanosomes that we named the acidocalcisome. This organelle is present in several trypanosomatids (T. cruzi, T. brucei, Leishmania spp.) and apicomplexan parasites (T. gondii, P. falciparum). The discovery of novel enzymes in this organelle that are absent from mammalian cells led to the finding of compounds (bisphosphonates) that produced radical cures in animal models of diseases caused by several parasites. We have recently identified the presence of a contractile vacuole complex in T. cruzi and we have demonstrated that acidocalcisomes of T. cruzi are involved, through their association with this contractile vacuole, in osmoregulation. T. cruzi possess a robust regulatory volume decrease mechanism that completely reverses cell swelling when submitted to hypo- osmotic stress. The efflux of amino acids and K+ release could account for only part of this volume reversal. Swelling of acidocalcisomes together with a microtubule and cyclic AMP-mediated translocation of an aquaporin to the contractile vacuole and the resulting water movement are responsible for the volume reversal not accounted for by efflux of osmolytes. Osmoregulation is essential for T. cruzi since the parasite is in contact with a variety of osmotic stresses during its life cycle. We propose that further exploration of the osmo-regulatory mechanisms in T. cruzi, and the role of the acidocalcisome and the contractile vacuole complex in these mechanisms, will lead to the identification of further targets for drug action. In this project we will have the following specific aims:
Specific aim 1 : To identify the signaling pathways involved in sensing osmotic changes in T. cruzi.
Specific aim 2 : To identify the molecular mechanism involved in the traffic T. cruzi aquaporin to the contractile vacuole complex and the role of aquaporin in regulatory volume decrease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068647-02
Application #
7188973
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$357,328
Indirect Cost
Name
University of Georgia
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
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Porcel, Betina M; Denoeud, France; Opperdoes, Fred et al. (2014) The streamlined genome of Phytomonas spp. relative to human pathogenic kinetoplastids reveals a parasite tailored for plants. PLoS Genet 10:e1004007
Docampo, Roberto; Jimenez, Veronica; Lander, Noelia et al. (2013) New insights into roles of acidocalcisomes and contractile vacuole complex in osmoregulation in protists. Int Rev Cell Mol Biol 305:69-113
Galizzi, Melina; Bustamante, Juan M; Fang, Jianmin et al. (2013) Evidence for the role of vacuolar soluble pyrophosphatase and inorganic polyphosphate in Trypanosoma cruzi persistence. Mol Microbiol 90:699-715
Jimenez, Veronica; Docampo, Roberto (2012) Molecular and electrophysiological characterization of a novel cation channel of Trypanosoma cruzi. PLoS Pathog 8:e1002750
Docampo, Roberto; Lukes, Julius (2012) Trypanosomes and the solution to a 50-year mitochondrial calcium mystery. Trends Parasitol 28:31-7
Li, Zhu-Hong; De Gaudenzi, Javier G; Alvarez, Vanina E et al. (2012) A 43-nucleotide U-rich element in 3'-untranslated region of large number of Trypanosoma cruzi transcripts is important for mRNA abundance in intracellular amastigotes. J Biol Chem 287:19058-69
Li, Zhu-Hong; Alvarez, Vanina E; De Gaudenzi, Javier G et al. (2011) Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi. J Biol Chem 286:43959-71
Schoijet, Alejandra C; Miranda, Kildare; Medeiros, Lia Carolina Soares et al. (2011) Defining the role of a FYVE domain in the localization and activity of a cAMP phosphodiesterase implicated in osmoregulation in Trypanosoma cruzi. Mol Microbiol 79:50-62
Pace, Douglas A; Fang, Jianmin; Cintron, Roxana et al. (2011) Overexpression of a cytosolic pyrophosphatase (TgPPase) reveals a regulatory role of PP(i) in glycolysis for Toxoplasma gondii. Biochem J 440:229-40

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