Faculty
Jan S Fassler Ph.D.
S. cerevisiae is an important model for the study of environmental stress responses. My interest has been in probing the influence of the environment on the physical characteristics of cells by studying adaptive changes in transcription. All cells have the capacity to precisely modulate the transcriptome, changing the levels at which specific genes are expressed in order to ensure survival in the face of specific challenges or changes in the environment. The response to oxidative stress is critical for preserving cellular integrity in an aerobic environment. Cellular damage resulting from oxidative stress has been implicated in normal cellular processes such as apoptosis, and aging as well as in a host of pathological conditions from Down\'s syndrome to cancer. The S. cerevisiae transcription factors Yap1p and Skn7p directly trigger activation of many of the OSR (oxidative stress response) target genes. Although activation of Yap1p upon oxidative stress has been extensively investigated, little is known about the activation of Skn7p during this process. Our preliminary work on this subject identified several threonine residues in the Skn7 receiver domain as likely phosphorylation sites and showed their importance in the interaction with Yap1p. We are also interested in the identification and characterization of molecules contributing to the oxidative stress responsiveness of Skn7p. Finally, we plan to investigate the hypothesis that Skn7p may play a specific role in sensing and responding reactive oxygen species generated in the mitochondria. In addition to oxidative stress, fluctuation in the external osmotic environment is a common challenge for cells. The molecular mechanism of osmotic stress sensing has important health implications in higher organisms where osmolality is closely linked not only to kidney medulla function, but also to vascular volume, levels of cardiac output and arterial pressure. Extensive parallels between the yeast and mammalian stress activated MAP kinase pathways suggest that yeast based insights into the molecular mechanism of osmotic stress signal transduction are likely to be general. The yeast stress-activated MAP kinase pathway responsible for osmosensing is regulated by Sln1. The activity of Sln1p is diminished in response to hypertonic stress and increased in response to hypotonic stress. Bifurcation of the pathway downstream of Sln1p leads to distinct stress-specific reprogramming of gene expression; hypertonic conditions lead to accumulation of compatible solutes via a p38 like MAP kinase cascade, whereas hypotonic conditions elicit changes in cell surface properties by direct aspartyl phosphorylation of the Skn7 transcription factor. Our work focuses on understanding how Sln1p interacts with its subcellular environment to sense and respond to changes in the external milieu; determining how phosphorylation of the SLN1-dependent transcription factor, Skn7p leads to specific activation of osmotic response genes; and characterizing the division of labor and/or overlap between the SLN1-SKN7 and the PKC cell wall integrity pathways in their efforts to ensure cellular integrity. Characterizing the mechanics of the yeast Sln1p sensor-kinase is likely to contribute new perspectives on the process by which eukaryotic cells maintain osmotic homeostasis.
Michael Feiss M.S., Ph.D.
We study how a virus, the E. coli bacteriophage lambda, packages DNA during assembly of the virion. We are interested in DNA-protein interactions involved in recognition, processing and packaging of the lambda chromosome. For recognition of lambda DNA, terminase, the viral DNA packaging protein, binds to a site on lambda DNA called cosB. Terminase also (1) binds the prohead, the empty protein shell into which DNA is to be packaged, (2) nicks the DNA at a site called cosN, to generate the cohesive ends of virion DNA, and (3) is thought to be involved in hydrolyzing ATP as a source of energy to translocate the DNA into the prohead. Current projects include a study of the interaction of cosB with terminase during recognition. We are also interested in the mechanism of DNA translocation. To study translocation, we are examining terminase mutants with specific defects in translocation. We use genetic and biochemical approaches in these studies.
John H. Fingert M.D., PhD.
My laboratory studies the molecular genetic basis of glaucoma and other inherited eye diseases using a range of patient-based research techniques. We have focused our genetic research on glaucoma because this condition is a leading cause of blindness and visual disability worldwide and there is a strong genetic component to its pathogenesis. My laboratory has ongoing projects to identify new glaucoma genes using both pedigree-based positional cloning approaches and population-based association studies. We are also conducting population-based studies of intraocular pressure and other quantitative traits of glaucoma including investigations to identify the genetic basis of patient response to drugs (pharmacogenomics). The ultimate goal of our research is to translate laboratory investigations into useful genetic tools for clinicians by developing genetic tests and providing insights needed for the development of the next generation of therapies to help prevent blindness.
Joseph Frankel Ph.D.
The goal of my research is to identify and characterize general mechanisms of pattern formation that are not dependent on multicellularity. This aim is being pursued through analyses of the spatial organization of cell surface structures in a ciliated protozoan, Tetrahymena. We had been pursuing this aim primarily through a genetic approach, seeking to induce and analyze mutations that affect the arrangement and organization of cell-surface structures. Our attention has been concentrated on mutations that affect the global spatial coordination of these structures. These mutations include a class, collectively known as a janus, that converts the dorsal surface of the cell into a partial mirror image of the ventral surface, and hypoangular, which reduces the distance between two sets of structures normally far apart. We have also discovered that wild-type cells can propagate mirror-image configurations of major cortical landmarks, which we call \"right-handed\" (RH) and \"left-handed\" (LH) respectively. I recently have been moving toward molecular biological approaches to patterning in ciliates. Most recently, in collaboration with Prof. Norman E. Williams, I have helped to characterize the phenotype of transformed cells containing \"disruption cassettes\" for genes encoding important cytoskeletal components, such as actin. I am also involved in collaborations with colleagues at other universities on problems of ciliate development and evolution. In the future, I hope to return to the cortical-pattern mutations, completing the description of the phenotype of unpublished mutations in my collection and possibly proceed toward cloning some of these genes as the technology becomes available and collaborations become feasible
