The Brendan Cormack Laboratory studies fungal pathogenesis, particularly the host-pathogen interaction for the yeast pathogen Candida glabrata. We are trying to identify virulence genes (genes that evolved in response to the host environment) by screening transposon mutants of C. glabrata for mutants that are specifically altered in adherence to epithelial cells, in survival in the presence of macrophages and PMNs. We also screen mutants directly in mice for those unable to colonize or persist in the normal target organs (liver, kidney and spleen). We also focus research on a family of genes--the EPA genes--that allow the organism to bind to host cells. Our research shows that a subset of them are able to mediate adherence to host epithelial cells. We are trying to understand the contribution of this family to virulence in C. glabrata by figuring out what the ligand specificity is of different family members, how genes are normally regulated during infection, and what mechanisms normally act to keep the genes transcriptionally silent and how that silence is regulated.

The Rao Laboratory studies the roles of intracellular cation transport in human health and disease using yeast as a model organism. Focus areas include intracellular Na+(K+)/H+ exchange and Golgi CA2+(MN+) ATPases.

Research in the Claypool Lab is focused on defining how lipids and membrane proteins interact to establish and maintain normal mitochondrial function and how derangements in this complex relationship result in pathophysiology. We have demonstrated that yeast lacking tafazzin recapitulates all of the phospholipid abnormalities observed in human patients and many of the mitochondrial defects. Another major project in our lab focuses on the mitochondrial ADP/ATP carrier that is required for oxidative phosphorylation. Researchers are studying how these novel interactions help establish normal mitochondrial function, the biochemical details of these associations, and whether disturbances in these assemblies can contribute to mitochondrial dysfunction.

The Michaelis Laboratory's research goal is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry and high-throughput genomic approaches. Our team studies the cell biology of lamin A and its role in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Other research focuses on the core cellular machinery involved in recognition of misfolded proteins. Understanding cellular protein quality control machinery will ultimately help researchers devise treatments for protein misfolding diseases in which degradation is too efficient or not enough.

Our research is focused on understanding the basic mechanisms of programmed cell death in disease pathogenesis. Billions of cells die per day in the human body. Like cell division and differentiation, cell death is also critical for normal development and maintenance of healthy tissues. Apoptosis and other forms of cell death are required for trimming excess, expired and damaged cells. Therefore, many genetically programmed cell suicide pathways have evolved to promote long-term survival of species from yeast to humans. Defective cell death programs cause disease states. Insufficient cell death underlies human cancer and autoimmune disease, while excessive cell death underlies human neurological disorders and aging. Of particular interest to our group are the mechanisms by which Bcl-2 family proteins and other factors regulate programmed cell death, particularly in the nervous system, in cancer and in virus infections. Interestingly, cell death regulators also regulate many other cellular processes prior to a death stimulus, including neuronal activity, mitochondrial dynamics and energetics. We study these unknown mechanisms. We have reported that many insults can trigger cells to activate a cellular death pathway (Nature, 361:739-742, 1993), that several viruses encode proteins to block attempted cell suicide (Proc. Natl. Acad. Sci. 94: 690-694, 1997), that cellular anti-death genes can alter the pathogenesis of virus infections (Nature Med. 5:832-835, 1999) and of genetic diseases (PNAS. 97:13312-7, 2000) reflective of many human disorders. We have shown that anti-apoptotic Bcl-2 family proteins can be converted into killer molecules (Science 278:1966-8, 1997), that Bcl-2 family proteins interact with regulators of caspases and regulators of cell cycle check point activation (Molecular Cell 6:31-40, 2000). In addition, Bcl-2 family proteins have normal physiological roles in regulating mitochondrial fission/fusion and mitochondrial energetics to facilitate neuronal activity in healthy brains.

Dr. Ross and his research team have focused on Huntington's disease and Parkinson's disease, and now are using insights from these disorders to approach more complex diseases such as schizophrenia and bipolar disorder. They use biophysical and biochemical techniques, cell models, and transgenic mouse models to understand disease processes, and to provide targets for development of rational therapeutics. These then can provide a basis for developing small molecule interventions, which can be used both as probes to study biology, and if they have favorable drug-like properties, for potential therapeutic development. We have used two strategies for identifying lead compounds. The first is the traditional path of identification of specific molecular targets, such as enzymes like the LRRK2 kinase of Parkinson’s disease. Once structure is known, computational approaches or fragment based lead discovery, in collaboration, can be used. The second is to conduct phenotypic screens using cell models, or in a collaboration, natural products in a yeast model. Once a lead compound is identified, we use cell models for initial tests of compounds, then generate analogs, and take compounds that look promising to preclinical therapeutic studies in animal models. The ultimate goal is to develop therapeutic strategies that can be brought to human clinical trials, and we have pioneered in developing biomarkers and genetic testing for developing strategies.

We leverage both yeast and mammalian systems to study the processes of mRNA translation and mRNA stability.