Our ability to predict when and where new infectious diseases will emerge depends on a more complete understanding of the factors that favor the evolutionary transition from microorganisms that are non-pathogenic to a state capable of causing sustained infection in humans. In this area three research groups are using comparative genomic approaches to study how bacteria become specifically adapted to different host-specific lifestyles. For example, in the case of Vibrio, much of the work in the Whistler and Cooper groups capitalizes upon the fact that within the species of Vibrio, there are both highly evolved symbionts and pathogens that share characteristics necessary for both types of colonization, but certain species have further refined their host-interactions through the horizontal acquisition of genes, some symbiosis factors, and some virulence factors. In ongoing NIH projects, these researchers are using a combination of comparative transcriptomics and genomics to define the genetic characteristics that determine whether the outcome of interaction is benign or harmful. Similarly, microbe-nematode systems are being investigated by both the Tisa and Cooper laboratories with a focus on understanding symbiosis and pathogenesis. The use of microbe-insect and microbe-nematode systems as models to study pathogenesis has been rapidly increasing and enabled by access to complete genome sequences from these emerging models ideal for investigating these questions. Advances in genomics have transformed the investigation of pathogenesis, and these research groups have rapidly adopted the new tools and will greatly benefit from the proposed expansion of the HCGS.
The source of all genetic variation is mutation. As such, the mechanisms dedicated to maintaining the fidelity of genome replication are fundamental to biology. The importance of this field has increased with the finding (based on whole genome analysis) that genome instability is a common aspect of many diseases such as cancer. DNA is continually altered by mutagenic agents from the environment (e.g. UV light, radiation etc.) and cellular metabolism (e.g. reactive oxygen). Because the types of damage to DNA are so diverse, it is not surprising that the mechanisms and molecular pathways that monitor and repair DNA damage are very complex and very well-conserved, from single-celled microorganisms (such as yeasts), to plants, to humans. The Thomas Lab has a long-standing research program using mutation accumulation lines in diverse organisms to investigate the baseline patterns of mutation in the relative absence of natural selection. The Culligan group focuses on the mechanisms that protect genes and genomes from excess DNA damage and mutation, using the plant Arabidopsis thaliana as a model system. Feixia Chu has recently joined the faculty in the HCGS. Dr. Chu uses mass spectrometric and cell biology approaches to reveal structural alterations on chromatin for genome maintenance and epigenetic dysregulation in cancer. Dr. Dowd is actively developing her skills in statistical genomics with a focus on developing efficient statistical approaches to the analysis of genetic variation for discovery of signatures of positive selection.
We are interested in developing and applying sophisticated mass spectrometric techniques to address complex biological questions. The ability for sensitive detection, specific structural elucidation, and quantitative measurement of biomolecules in a systematic and high through-put manner has enabled mass spectrometry to emerge as a core proteomic technology. Mass spectrometric analyses help us to reveal some essential properties of proteins, including their expression levels, posttranslational modifications, and sequences of various forms, as well as their spatially and temporally regulated interactions. Specific biological questions we are currently tackling include determining the sequences of novel reproduction neurohormones (Sower), identification of substrates for particular enzymes (Collins & Hrabak), structural elucidation of protein interaction surfaces (Cote & Denis), characterization of viral-related protease cleavage of translation factors (Denis), and the identification and characterization of the nature and function of modifications on chromatin associated proteins (Chu). In addition, we are developing and expanding the biochemical and bioinformatic tools repertoire necessary for the complex and challenging nature of these and other biological questions (Chu).
The Glycomics Center is an integrated Biotechnology Research Resource built around advanced techniques in mass spectrometry, bioinformatics, and glycomics function. Central applications at the Glycomics Center include analysis of therapeutic glycoprotein drugs, avian influenza in relation to viral receptors, studies of cancer biology with murine models and discovery of possible biomarkers of malignancy. Supporting these efforts are developments in analytical protocols, and bioinformatics that have aspirations for automation and high throughput analysis. These broad based activities bring together researchers, teachers and students in biochemistry, genetics, cell biology, chemistry, biotechnology, computational biology and medicine. In supporting these projects, the Glycomics Center provides the instrumentation and computational resources required to address research efforts lying at the center of these multiple disciplines.
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