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Department of Pharmacology

Department of Pharmacology

Angela Gelli, Ph.D.

Angela Gelli, Ph.D.

Associate Professor
Ph.D., University of
Toronto, 1997
(530) 754-6446
e-mail

Education

B.Sc., 1990 Chemistry - Biochemistry, University of Toronto, Canada
M.Sc., 1992 Electrophysiology, University of Toronto, Canada
Ph.D., 1997 Cell Biology / Electrophysiology, University of Toronto, Canada.

Research Interests

Virulence determinants of fungal pathogenesis

Research Synopsis

Cryptococcus neoformans is a human fungal pathogen that causes an invasive and life-threatening infection primarily in patients with a compromised immune system. Once cryptococcal cells disseminate into the bloodstream, they cross the blood-brain barrier (composed of the brain endothelium) and cause meningoencephalitis, an often-deadly infection. C. neoformans is now the leading cause of fungal meningitis world-wide and accounts for a significant proportion of AIDS-related infections. How cryptococcal cells manage to breach the blood-brain barrier and enter the brain is not fully understood. Through the use of proteomics, molecular biology and an in vitro model of the blood-brain barrier, we are identifying and examining the role of several key surface proteins of Cryptococcus in breaching the barrier and promoting brain invasion. Since we believe that the relationship between cryptococcal cells and the brain endothelium is highly dynamic we are identifying the temporal protein expression profiles of the brain endothelium in response to C. neoformans. We anticipate that these studies will lead to an understanding of the mechanisms that promote the invasion of cryptococcal cells into the CNS, which we can then manipulate and exploit for the delivery of drugs into the brain to treat brain cancers and neurodegenerative diseases. In addition, the identification of key proteins (either on the pathogen or the brain endothelium) that facilitate CNS invasion may lead the way to the development of drugs that prevent fungal meningitis.

Treating a cryptococcal infection in an immunosuppressed individual is challenging in part because some of the best antifungal drugs (like azoles) are not fungicidal. We have characterized a calcium channel (Cch1-Mid1) in the plasma membrane of Cryptococcus neoformans that appears to be a promising target for the development of small molecules that could be used in combination to promote fungicidal activity of azoles. We are performing a high-throughput screen to identify molecules that target the channel and we expect to identify several new molecules that will have clinical relevance. We have also used a multidisciplinary approach (electrophysiology, molecular biology and cell biology) to characterize the role of this calcium channel in the pathogen. We found that cryptococcal cells require this channel when trying to survive in environments that are low in calcium such as macrophages. We have also performed the first mechanistic study of this calcium channel and found that it functions as a store-operated calcium selective channel that is essential for the survival of cryptococcal cells during ER (endoplasmic reticulum) stress. The ability of the channel to get to the plasma membrane where its function is required is dependent on a secondary protein, elongation factor 3. This protein has been of interest for a long time because it is an essential protein and it does not have a human homologue making it the perfect antifungal drug target. We are currently exploring how and when the two proteins associate and resolving the molecular mechanism of their interaction.

Selected Publications

Pantoaja O., Gelli A., Blumwald, E.  (1992)  Voltage-dependent calcium channels in plant vacuoles.  Science, 255, 1567-1570.  Abstract.

Pantoja, O., Gelli, A., Blumwald, E.  (1992).  Characterization of vacuolar Malate and Potassium channels under physiological conditions.  Plant Physiol. 100, 1137-1141.  Abstract.

Gelli, A.  & Blumwald, E.  (1993).  Calcium retrieval from vacuolar pools.  Characerization of a vacuolar calcium challen.  Plant Physiol.  102,1139-1146.  Abstract.

Plant P., Gelli, A., Blumwald E. (1994)  Vacuolar chloride regulation of an anion selective tonoplast channel.  J. Membrane Biol. 140, 1-12.  Abstract. 

Gelli, A., Higgins, V.J. & Blumwald, E. (1997).  Activation of plant plasma membrane CA2+-permeable channels by race-specific fungal elicitors.  Plant Physiol.  13, 269-279.  Abstract.

Gelli, A. & Blumwald, E. (1997).  Hyperpolarization-activated Ca2+ - permeable channels in the plasma membrane of tomato cells.  J. Membrane Biol.  155,35 45.  Abstract.

Blumwald E., Gelli A.  (1997)  Secondary inorganic ion transport in plant vacuoles.  Adv. Bot. Res. 25, 401-417.

Gelli A., Aharon, G.S., Snedden W.A., Blumwald E.  (1998)  Activation of plasma membrane Ca2+ channel by TGalpha1, a heterotrimeric G protein alpha-subunit homologue.  Abstract.  

Higgins V.J., Lu H., Xing T., Gelli A., Blumwald E.  (1999).  The gene for gene concept and beyond:  Interactions and SIgnals, Can. J. Plant Pathol.  20, 150-157.  Abstract.

Gelli, A. (2002). Rst1 and Rst2 are required for the a/alpha diploid cell type in yeast. Mol Microbiol 46:845-854. Abstract.

George, M.D., Samarkan, S., E. Reay, Gelli, A., Dandekar, S. (2003). High throughput gene expression profiling indicates loss of intestinal growth factors and cell cycle mediators during primary simian immunodeficiency virus infection. J Virol 312:84-94. Abstract.
 
Sottosanto, J., Gelli, A. and Blumwald E. (2004).  DNA array analyses of Arabidopsis thaliana lacking a vacuolar Na+/H+ antiporter: Impact of AtNHX1 on gene expression.  Plant Journal 5, 751-771. Abstract.

Liu M., Du P., Heinrich G., Cox G.M., Gelli A.  (2006).  Cch1 mediates calcium entry in Cryptococcus neoformans and is essential in low calcium environments.  Eukaryotic Cell.  Abstract.

Eigenheer, R. A., Lee, Y. J., Blumwald, E., Phinney, B. S., and Gelli A. (2007) Extracellualr GPI-anchored mannoproteins and proteases of Cryptococcus neoformans. FEMS Yeast Research, 7:499-510.

Liu M, and Gelli A. (2008) Elongation factor 3, EF3, associates with the Ca2+ channel Cch1, and targets Cch1 to the plasma membrane of C. neoformans. Eukaryotic Cell 7:1118-1126.

Gelli, A. (2008) Gene regulation and signaling. 7th International Conference on Cryptococcus and Cryptococcosis, European Confederation of Medical Mycology, December, (www.ecmm.eu).

Vu, K., and Gelli A. (2009) Fungicidal activity of fluconazole with astemizole and its analogues against Cryptococcus neoformans var. grubii and Cryptococcus gattii. Med Mycology I-8 (doi: 10.1080/13693780903081968).

Vu K, Bautos J, Hong MP and Gelli A (2009) The functional expression of toxic genes: Lessons learned from molecular cloning of CCH1, a high-affinity calcium channel. Analytical Biochem 393:234-241 (doi:10.1016/j.ab.2009.06.039).

Vu K, Weksler B, Romero I, Couraud PO, Gelli A. (2009) An immortalized human brain endothelial cell line HCMEC/D3, as a model of the blood-brain barrier facilitates in vitro studies of CNS infection by Cryptococcus neoformans. In press, Eukaryotic Cell (doi:10.1128/EC.00240-09).

Hong MP, Vu K, Bautos J, and Gelli A. (2010) Cch1 restores intracellular Ca2+ in fungal cells during endoplasmic reticulum stress. In press, Journal of Biological Chemistry.

See: Complete List of Publications