Silvia N. J. Moreno
Professor, Department of Cellular Biology

Office:
350 Coverdell Center
706-542-4736s
moreno@cb.uga.edu

Lab:
360 Coverdell Center
706-583-0181

Lab Homepage

Research Overview

Our work is centered in the characterization of metabolic pathways in Toxoplasma gondii and Trypanosoma cruzi, and more specifically in the mechanisms regulating calcium (Ca2+) homeostasis in these parasites, and in the characterization of the isoprenoid pathway as a target for antiparasitic drugs. A variety of cellular functions are regulated by fluctuations of the cytosolic concentration of Ca2+. The intracellular Ca2+ concentration [Ca2+]i is maintained at very low levels (of the order of 10-7 M) compared with those in the extracellular medium (about 10-3 M). The total calcium inside the cell is much higher than 10-7 M, but the bulk of this calcium is either bound to proteins, membranes or other cellular constituents, or is sequestered inside intracellular organelles such as mitochondria, endoplasmic reticulum, Golgi apparatus, and nuclei. Calcium homeostatic mechanisms in T. gondii and T. cruzi have distinct peculiarities, such as the presence of an organelle rich in calcium bound to polyphosphate that we named the acidocalcisome. We are currently investigating the chemical and enzymatic composition of these organelles as well as their role in calcium homeostasis in T. gondii. One important enzyme that is present in the acidocalcisomes is the vacuolar proton pyrophosphatase. This enzyme is inhibited by pyrophosphate analogs (bisphosphonates) so this led us to think that these compounds might inhibit parasite growth. This was the case but later we found that one important target for the action of many other bisphosphonates was the isoprenoid pathway and then we started to work on the characterization of this pathway. Bisphosphonates offer a potential new route to chemotherapy against parasitic diseases. An essential enzyme involved in calcium homeostasis in T. cruzi is a phosphatidylinositol phospholipase C. This enzyme is the only known phospholipase C modified by N-myristoylation and palmitoylation and is essential for differentiation of these parasites.

Ongoing projects in the laboratory:

  1. Study of the composition, and function of acidocalcisomes in Toxoplasma gondii; Polyphosphate metabolism Calcium pools Proteomic analysis of purified acidocalcisomes
  2. The isoprenoid pathway as a target for anti-Toxoplasma drugs.
  3. Study of the role of the inositol phosphate/diacylglycerol signaling pathway in Trypanosoma cruzi

Representative Publications

Shuhong L., Vieira, M. A., Zhong, L, Graves, J., and Moreno S.N.J. (2001) Cloning, functional expression and co-localization of the vacuolar Ca2+-ATPase with a vacuolar H+-pyrophosphatase to acidocalcisomes of Toxoplasma gondii EMBO J. 20, 55-64. pdf

Lovett, JL, Marchesini,N. Moreno, S.N.J. Sibley, L.D. (2002) Toxoplasma gondii microneme secretion involves intracellular Ca2+ release from IP3/ryanodine sensitive stores. J. Biol. Chem. 277, 25770-25876. pdf

Rodrigues, C.O., Ruiz, F.A., Rohloff, P., Scott, D.A., and Moreno, S.N.J. (2002) Characterization of isolated acidocalcisomes from Toxoplasma gondii tachyzoites reveals a novel pool of hydrolysable polyphosphate. J. Biol. Chem. 277, 48650-48656. pdf

Salto, M. L., Bertello, L. E. Vieira, M.C.F., Docampo, R., Moreno, S.N.J., Lederkremer, R.M. (2003). Formation and remodeling of inositolphosphoceramide during the differentiation of trypomastigote into amastigote forms of Trypanosoma cruzi. Eukaryotic Cell 2, 756-768. pdf

Moreno, S.N.J., and Docampo, R. (2003) Calcium regulation in protozoan parasites. Curr. Opinion Microbiol., 6:359-364. pdf

Arrizabalaga, G., Ruiz, F., Moreno, S.N.J. and Boothroyd, J.A. (2003) Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a sodium/hydrogen exchanger in calcium regulation. J. Cell Biol. 165:653-662. pdf

Docampo, R., de Souza, W., Miranda, K., Rohloff, R., and Moreno, S.N.J. (2005) Acidocalcisomes –conserved from bacteria to man. Nat. Rev. Microbiol. 3:251-261. pdf

Ling, Y., Sahota, G., Odeh, S., Chan, J.M., Araujo, F., Moreno, S.N.J. and Oldfield, E. (2005) Bisphosphonate inhibitors of Toxoplasma gondii growth: in vitro, QSAR and in vivo investigations. J. Med. Chem, 48:3130-3140. pdf

Luo, S., Ruiz, F.A., and Moreno, S.N.J. (2005) The acidocalcisome Ca2+-ATPase (TgA1) of Toxoplasma gondii is required for polyphosphate storage, intracellular calcium homeostasis and virulence. Mol. Microbiol. 55:1034-1045. pdf

Okura M, Fang J, Salto ML, Singer RS, Docampo R, Moreno S.N.J. (2005) A lipid-modified phosphoinositide-specific phospholipase C (TcPI-PLC) is involved in differentiation of trypomastigotes to amastigotes of Trypanosoma cruzi. J Biol Chem. 280:16235-43. pdf

Fang J, Marchesini N, Moreno S.N.J. (2006) A Toxoplasma gondii phosphoinositide phospholipase C (TgPI-PLC) with high affinity for phosphatidylinositol. Biochem J. 394:417. pdf

Ling Y, Li ZH, Miranda K, Oldfield E, Moreno SN. (2007) The farnesyl diphosphate/geranylgeranyl diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and the molecular target of bisphosphonates. J. Biol. Chem. in press