研究领域

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Detection and Response to Osmotic and Oxidative Stress in Saccharomyces cerevisiae. Environmental stress sensing and signal transduction in fungi; Antifungal drug leads. At the molecular level successful adaptation of organisms to the environment involves multiple steps including (1) recognition of external signals and their conversion into intracellular information (signal transduction); (2) binding of specific adaptive gene promoters by appropriate transcription factors and (3) transcriptional activation via transcription factor - core promoter transcriptional machinery interactions. We use the single-cell model eukaryote, Saccharomyces cerevisiae (yeast), and the opportunistic pathogen, Cryptococcus neoformans, to investigate these themes using genetic screens, biochemical assays, and transcriptome analysis. We also capitalize on existing protein structure information for stress signaling molecule complexes in essential signal transduction pathways to design inhibitory peptides corresponding to the protein-protein interface. Even partial inhibition of activity is expected to substantially compromise fitness and virulence of fungal pathogens by simultaneously altering normal environmental stress responses. Identification of inhibitory peptides that are toxic to Cryptococcus may provide a foundation for isolating structurally related small molecule inhibitors and candidate lead compounds for novel antifungal drugs. The evolution of animals via gene loss. As emphasized by developmental biologist, Lewis Wolpert, in his famous quote: "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life", the morphogenetic process that organizes the multicellular body plan of animals into distinct layers and gives rise to nervous system, intestines, and musculature is a defining attribute of animals. While other organisms also evolved multicellularity, they neither gastrulate nor have the genes that drive this process. Thus, animal evolution research has thus far focused on genes unique to animals. In a collaborative project with the Erives laboratory we are taking advantage of the availability of full genome sequences from all domains of life and asking NOT what genes are uniquely present in animals, but instead what genes have been lost, and thus re-evaluating what it means to be an animal. Such gene losses may identify important constraints that interfered with the evolutionary innovation of new developmental programs or that were rendered superfluous. Poly-glutamine tract length variation in Gal11. Yeast GAL11 encodes a subunit of the RNA polymerase II mediator complex and plays important roles in eukaryotic transcriptional activation. The Gal11 protein is unusual in containing long tracts of glutamine (Q). Inspection of the GAL11 locus in many natural yeast strains with sequenced genomes reveals extreme variation in Q-rich regions, specifically. Thus, Q-rich proteins may encode an important source of genetic variation contributing to the rapid adaptation of strains to novel environments. We have introduced GAL11 variants from wine yeast strains with differing poly-Q content into laboratory strains to investigate the extent to which poly-Q variation affects Gal11 function and yeast strain fitness in stressful environments. The study of length variation in Q rich tracts is clinically important because numerous neurodegenerative disorders, known as triplet repeat diseases, are the result of expansion of the CAA or CAG codons for glutamine leading to an aggregation-prone protein conformation and cellular toxicity.

Evolution, Genetics