Proteomics

Dr. Vedantam’s research interests are broadly focused on pathogenic mechanisms leading to antibiotic-associated diarrhea, and include host-pathogen studies of the diarrheagenic agent Clostridium difficile. C. difficile infection is currently a leading healthcare-acquired disease in the USA, incurring over $3 billion in treatment and containment costs. Dr. Vedantam’s laboratory uses multiple genomic and proteomic approaches to study C. difficile pathogenesis, including, but not limited to, automated iTRAQ-based comparative proteomics, and genomic analyses. Her laboratory also offers hospital surveillance and typing services, and a genetic manipulation program for clostridial pathogens. These efforts have identified attractive targets for interventions aimed at eliminating C. difficile from the gut, and are a focus of translational research goals. Dr. Vedantam is also involved in multiple teaching efforts, and offers a highly popular, upper-division, laboratory-based course on bacterial pathogens. The strengths she brings to any research endeavor are based on her expertise in genetic, mechanistic and animal model studies. Keywords: Infectious Disease, healthcare-associated infections, bacterial pathogenesis

Dr. Schlenke's research program uses fruit flies in the genus Drosophila to understand the evolutionary genetics of host-parasite interactions. For example, his lab has developed several species of parasitic wasps, which are readily observed infecting Drosophila in nature and can be very specialized to particular host species, as model parasites. These wasps lay single eggs in Drosophila larvae and, once hatched, consume flies from the inside out. Flies mount cellular and behavioral defense responses against wasps, but wasps have adaptations for finding host fly larvae, suppressing host cellular immunity, and manipulating host behavior. The Schlenke lab uses a variety of "omics" tools to understand the molecular genetics of fly cellular immunity and wasp virulence, as well as patterns of host immunity and pathogen virulence coevolution across fly and wasp phylogenies. The Schlenke lab also studies the genetics and neurobiology of behaviors that flies use to avoid being infected by the wasps and to cure themselves once they are infected, including various self-medication behaviors.

William Montfort, PhD, determines the atomic structures of proteins and seeks to understand how protein structure gives rise to protein function – both in vitro and in living cells. At their heart, the problems have a fundamental structure-function question, but also address questions of importance to human health. Approaches include X-ray crystallography, rapid kinetic measurements, spectroscopy, theory, protein expression, drug discovery, molecular genetics and related techniques.Dr. Montfort is particularly interested in nitric oxide signaling mechanisms. Nitric oxide (NO) is a small reactive molecule produced by all higher organisms for the regulation of an immensely varied physiology, including blood pressure regulation, memory formation, tissue development and programmed cell death. He is interested in two NO signaling mechanisms: binding of NO to heme and the nitrosylation (nitrosation) of cysteines. NO, produced by NO synthase, binds to soluble guanylate cyclase (sGC) at a ferrous heme center, either in the same cell or in nearby cells. Binding leads to conformational changes in heme and protein, and to induction of the protein’s catalytic function and the production cGMP. NO can also react with cysteine residues in proteins, giving rise to S-nitroso (SNO) groups that can alter protein function. He continues to study the mechanistic details surrounding cGMP and SNO production, and the signaling consequences of their formation.For reversible Fe-NO chemistry, Dr. Montfort is studying soluble guanylate cyclase and the nitrophorins, a family of NO transport proteins from blood-sucking insects. Our crystal structures of nitrophorin 4 extend to resolutions beyond 0.9 angstroms, allowing us to view hydrogens, multiple residue conformations and subtle changes in heme deformation. For reversible SNO chemistry, he is studying thioredoxin, glutathione S-nitroso reductase (GSNOR) and also sGC. For regulation in the cell, Dr. Montfort and his group have constructed a model cell system based on a human fibrosarcoma called HT-1080, where sGC, NO synthase, thioredoxin and GSNOR can be manipulated in a functional cellular environment. With these tools, they are exploring the molecular details of NO signaling and whole-cell physiology, and undertaking a program of drug discovery for NO-dependent diseases. Keywords: Structural Biology, Drug Discovery, Cancer, Cardiovascular Disease

Membrane proteins play a number of critical biochemical roles and make up the majority of drug targets. Despite their importance, membrane proteins remain challenging systems for analysis due to their amphipathic nature and low expression levels. Moreover, the lipid bilayer can play an important but largely unexplored role in regulating membrane protein structure and function. New analytical and biochemical methods are necessary to better understand and design drugs to target membrane proteins.

Matthew Cordes, Ph.D. is an Associate Professor of Chemistry and Biochemistry at the University of Arizona College of Science. Dr. Cordes’ research focuses on the origin and evolution of new protein structures and functions. He has published approximately 30 original research papers and presents his work frequently at national meetings such as the Protein Society and Gordon Research Conferences on Proteins and Biopolymers. Dr. Cordes’ primary research contributions are in four fields of protein evolution. First, his laboratory has identified cases in which a new type of protein structure has evolved from a preexisting structure. Second, he has identified evolutionary codes by which proteins that bind specific sites on double-stranded DNA evolve to recognize new target sites. Third, he studies the evolution of proteins in bloodsucking insects and spiders that affect blood homeostasis or cause dermonecrotic effects in mammalian tissue. Finally, he uses bioinformatics to identify hidden patterns in protein sequences that allow them to fold correctly and avoid aggregation such as that which occurs in Alzheimer’s disease. Dr. Cordes presently holds a BIO5 pilot project seed grant to study the evolution of enzyme toxins in brown spider venom.

Andrew Capaldi, PhD, researches the signaling pathways and transcription factors in a cell that are organized into circuits. They allow cells to process information and make decisions. For Dr. Capaldi, the work arises in understanding both how these circuits are built from their components, and how they function and malfunction. To address these questions, he is working to reverse engineer the circuitry that controls cell growth in budding yeast using a combination of genomic, proteomic and computational methods. http://capaldilab.mcb.arizona.edu