Opportunistic infections remain the most important complication of infection with the Human Immunodeficiency Virus (HIV) and the principal cause of death in patients with the Acquired Immune Deficiency Syndrome (AIDS). A large proportion of patients infected with HIV develop severe oropharyngeal and esophageal candidiasis. The predominant infecting species, Candida albicans, can grow as yeast, pseudohyphae and hyphae and the ability to transition between these different cell types is important for virulence. Cell cycle progression, which is controlled by cyclin-dependent kinases, is often intimately connected to the regulation of morphogenesis. Our preliminary data indicate that the two C. albicans B-cyclins (Cyblp and Cyb99p) and a putative transcriptional regulator of cell cycle genes (Fkh2p) are important for distinct aspects of morphogenesis and that Fkh2p regulates the levels of Cyb99 mRNA. We will test four hypotheses: First, that the two C. albicans B-cyclins have distinct roles in cell cycle progression; second, that Fkh2p is a transcriptional regulator of B-cyclin and other cell cycle-regulated genes; third, that C. albicans hyphae have cell cycle dynamics more similar to filamentous fungi than to budding yeast; and fourth, that C. albicans morphogenesis involves specific, fundamental changes in cell cycle dynamics that are also important for virulence. We propose to identify and characterize C. albicans gene products that regulate both cell cycle progression and morphogenesis in order to reveal the molecular mechanisms that underlie the coordination of these processes. Specifically, we will determine the mechanisms by which the B-cyclins and Fkh2p contribute to morphogenesis, cell cycle regulation, and virulence. We will compare wild-type strains and strains lacking Fkh2p or B-cyclins using time-lapse microscopy of fluorescent proteins to follow the dynamics of cell cycle progression. We will use DNA microarrays to follow transcriptional regulation and in vitro aasays of interactions between the pathogen and epithelial tissue or macrophages to study aspects of virulence. Ultimately, fungal-specific gene products that execute essential cell cycle processes may be important new targets for the development of anti-fungal therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014666-03
Application #
6765845
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Lunsford, Dwayne
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$363,811
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Gerstein, Aleeza C; Rosenberg, Alexander; Hecht, Inbal et al. (2016) diskImageR: quantification of resistance and tolerance to antimicrobial drugs using disk diffusion assays. Microbiology 162:1059-68
Gladfelter, Amy; Berman, Judith (2009) Dancing genomes: fungal nuclear positioning. Nat Rev Microbiol 7:875-86
Berman, Judith (2009) Growth and development: eukaryotes. Curr Opin Microbiol 12:589-91
Gale, Cheryl A; Leonard, Michelle D; Finley, Kenneth R et al. (2009) SLA2 mutations cause SWE1-mediated cell cycle phenotypes in Candida albicans and Saccharomyces cerevisiae. Microbiology 155:3847-59
Finley, Kenneth R; Berman, Judith (2005) Microtubules in Candida albicans hyphae drive nuclear dynamics and connect cell cycle progression to morphogenesis. Eukaryot Cell 4:1697-711
Ihmels, Jan; Bergmann, Sven; Berman, Judith et al. (2005) Comparative gene expression analysis by differential clustering approach: application to the Candida albicans transcription program. PLoS Genet 1:e39
Ihmels, Jan; Bergmann, Sven; Gerami-Nejad, Maryam et al. (2005) Rewiring of the yeast transcriptional network through the evolution of motif usage. Science 309:938-40
Gerami-Nejad, Maryam; Hausauer, Danielle; McClellan, Mark et al. (2004) Cassettes for the PCR-mediated construction of regulatable alleles in Candida albicans. Yeast 21:429-36
Bensen, Eric S; Martin, Samuel J; Li, Mingchun et al. (2004) Transcriptional profiling in Candida albicans reveals new adaptive responses to extracellular pH and functions for Rim101p. Mol Microbiol 54:1335-51
Magee, P T; Gale, Cheryl; Berman, Judith et al. (2003) Molecular genetic and genomic approaches to the study of medically important fungi. Infect Immun 71:2299-309

Showing the most recent 10 out of 11 publications