Saturday, May 18, 2024
5/18/2024
Project Summary: The proposed research leverages recent technological breakthroughs to investigate aspects of pseudouridylation and pseudouridine degradation that distinguish C. albicans from humans. Increased resistance to the few treatment options available for C. albicans infection underscores the importance of understanding how fungal pathogens differ from humans at the molecular level. The proposed research addresses fundamental questions about C. albicans biology by investigating essential aspects of RNA metabolism and has the potential to identify novel antifungal targets. The long-term objective of the proposed research is to understand how RNA modification and processing differ between humans and pathogenic fungi. Pseudouridine is an RNA modification found in a wide variety of RNA molecules in all kingdoms of life. Although pseudouridine is widespread, the amount and mechanism by which pseudouridylation occurs varies tremendously between taxa. Preliminary data indicate C. albicans Pus7 is critical for biofilm formation and rRNA processing. The mechanisms by which Pus7 absence leads to these phenotypes has not been investigated. Undergraduate and masters students will identify Pus7 substrates and determine where it localizes in the cell. The data collected will begin to develop a model for Pus7’s role in vivo. When RNA is degraded, the pseudouridine C-C glycosidic bond is degraded by pseudouridine glycosidases and kinases. While highly conserved in bacteria and most fungi these enzymes are not present in mammals or members of the Saccharomyces fungal clade. Little is known about this family of enzymes and the experiments proposed will be the first characterization of these enzymes in fungi. Undergraduate and masters students in the Bernstein lab will knockout these enzymes and determine how this effects C. albicans phenotype. Students will examine how pseudouridine glycosidase and kinase transcription is regulated. C-C glycosidic bond cleavage is an enzymatic activity not found in mammalian cells, and as such could be an important therapeutic target. Answering these questions will demand students perform medically relevant experiments in an important human fungal pathogen. Students in the Bernstein lab will gain experience in a wide variety of fundamental molecular biology techniques including cutting-edge CRISPR genome-editing technology. Students will be directly supervised by Dr. Bernstein and will participate in experimental design, data collection, interpretation, and dissemination of results. Furthermore, portions of the experiments proposed will be incorporated into the laboratory components of two courses taught by Dr. Bernstein, exposing an additional 32 students to significant biomedical research every year. Undergraduate and masters students in the Bernstein laboratory and both classes will be positioned to make discoveries that have a direct impact on our understanding of fungal pathogenesis and human health. These experiences serve them well as they pursue careers and further education after graduation.
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