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(1) Mechanisms of RNA-guided genome defense
We investigate the biology and evolution of mechanisms that distinguish cellular genes from parasitic (or “selfish”) nucleic acids. We focus on mechanisms that silence selfish DNAs them using chromatin- and small RNA-based mechanisms. We use simple yeast model systems to study these questions in depth and to develop a general mechanistic understanding of the principles of selfish element recognition and silencing. Our recent studies have revealed unexpected role for noncoding RNAs including introns and the spliceosome in genome defense.
(2) Molecular basis of fungal virulence
We use a pathogenic yeast, Cryptococcus neoformans to study the mechanisms of fungal pathogenesis, particularly deadly fungal meningitis. C. neoformans is responsible for 1 million new infections annually, most of which result in death due to meningitis. As the only human pathogenic fungus with a complete sexual cycle and haploid genetics, this yeast offers unique experimental advantages. We seek to identify and characterize new mechanisms of virulence. We are also identifying new small molecules that can inhibit fungal growth or virulence. Our recent studies have elucidated a dense transcriptional networks and downstream effectors that control the ability of the pathogen to resist phagocytosis and cause disease.