Angela (Angie) C. Gelli
Assistant Professor

email: acgelli@ucdavis.edu

Specialty: Infectious Diseases

Undergraduate Education:

• University of Toronto
  Toronto, Ontario
  B.Sc. 1990
  University of Toronto
  Toronto, Ontario
  M.Sc. 1992

Other School:

• University of Toronto
  Toronto, Ontario
  Ph.D. 1997

Fellowships: Postdoctoral Fellowship, Mount Sinai Hospital, Natural Sciences & Engineering Research Council

Mechanisms of fungal adherence to the brain endothelium.
The scope of my research program examines the cell surface interactions between fungal pathogens and host that specifically promote the pathogenesis of human fungal infections. Cryptococcus neoformans is a medically relevant pathogen that causes lethal meningoencephalitis in immunocompromised individuals. Infection occurs by inhalation of acapsular yeast cells and if not contained in the lung, C. neoformans disseminates to bone, skin and particularly the brain. Despite the relevance of attachment-interactions for cryptococcal meningoencephalitis, virtually nothing is known about the mechanisms by which C. neoformans attaches to the brain endothelium and how these interactions promote the proliferation of C. neoformans within brain tissue. My research group is currently focused on the identification of virulence factors in the pathogen that mediate adherence to the brain endothelium (blood brain barrier) and promote pathogen proliferation in the host. In order to identify signaling proteins that mediate adherence of fungal cells to the brain endothelium, we have initiated a primary cell line of brain microvascular endothelial cells from SIV-infected rhesus macaques. These primary cultures will be used to identify proteins in cells of C. neoformans that specifically mediate endothothelium-adherence. Combinatorial peptide libraries, created by my research group, along with two-hybrid screens and proteomics will be used to identify key proteins. This approach of investigation has direct application to anti-fungal drug discovery since virulence factors often make very good drug targets. In addition, any insight gained from examining the mechanism of fungal adherence to- and penetration of the brain endothelium may provide researchers with a means to specifically transport drugs across the blood brain barrier and into the brain parenchyma where they could be used to battle brain degenerative diseases.

Calcium-calcineurin dependent signaling in fungal pathogenesis.
Among the signal transduction pathways that are believed to be involved in the proliferation of C. neoformans in the host, is a calcium-calcineurin signaling pathway. We have currently identified and cloned a plasma membrane calcium channel in C. neoformans that is required for fungal virulence. We are currently performing structure-function studies of the calcium channel. In addition we are using GST-pull down experiments and two-hybrid analysis to find proteins that specifically associate with the calcium channel during fungal pathogenesis. We anticipate that our research will reveal a link between calcium channels and calcineurin activation, furthering our understanding of the calcium-dependent signaling pathway in pathogen proliferation during host colonization. This finding has direct application to drug discovery, since this calcium channel may prove to be a viable drug target. Prior to this finding, calcium channels in fungal pathogens had not been characterized nor cloned. Since calcium channels in fungal pathogens have never been characterized at the level of detail that the biophyics/electrophysiology approach will allow, we anticipate that our research will likely produce the first mechanistic insight into calcium channel activity in the entire pathogenic fungal kingdom.

Selected Publications: Gelli *, A., Aharon*, G.S., Snedden, W.A. & Blumwald, E. (1998). Activation of a plasma Membrane Ca2+ channel by TGa1, a heterotrimeric G protein a-subunit homologue. FEBS Let. 424:17-21. (*shared first authorship)

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

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

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. (in press, J Virol).

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

George, Michael D., Sankaran, Sumathi, Reay, Elizabeth, Gelli, Angie C. and Dandekar, Satya. 2003. High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection. Virology. 312:84-94.