The numbers of published papers on oxidative stress and its impacts on health and disease has expanded an order of magnitude over the past decade, underscoring the fundamental importance of this research area in a comprehensive program to address molecular mechanisms of disease. Research in redox biology includes the study of reduction-oxidation events in metabolism, signaling pathways, stress response, and cellular repair that are essential for growth and development. The Redox Biology Center is an internationally recognized leader in redox biology and has developed innovative, multi-disciplinary, and multi-campus research programs. The Center continues to mentor new investigators and develop research infrastructure to advance all aspects of the basic and translational questions surrounding redox biology in health and disease. The Center has a critical mass of NIH-funded research in diverse fields, and provides unique training opportunities in this area to students within and outside the MMoD program. This mentor team is investigating how critical redox buffers are generated, maintained, and manipulated to alter cellular physiology, which is relevant to cancer and neurogenerative diseases and is integral to research in all other emphasis areas in this proposal. Mass spectrometric and structural/biophysical methods of analyzing individual proteins that modulate stress impacts lend exceptionally powerful quantitative approaches to this training emphasis.
Charles Bessey Professor of Biochemistry, Redox Biology Center Director
Research focus: Role of proline in redox homeostasis and apoptosis.
Proline is an important amino acid for protein synthesis, particularly incorporation into fibrous architectural proteins such as collagen, and also for cellular redox balance and protection against oxidative stress. In humans, aberrant proline metabolism due to genetic loss of its biosynthetic or degradative enzymes leads to neurological disorders, skin hyperplasticity, and osteopenia. Reactive oxygen species (ROS) generated from proline oxidation have been shown to induce cell signaling processes that impact cell survival and cell death. Proline-dependent ROS signaling induces apoptosis and suppresses tumor growth, whereas under different metabolic conditions, proline has been shown to increase cell growth and tumor survival. Understanding the complex regulation of proline metabolism in cancer and the mechanisms by which proline metabolism influences intracellular redox homeostasis and ROS signaling is a major effort of Dr. Becker's laboratory. Students in Dr. Becker's laboratory are working on projects related to the detailed biochemical characterization and comparison of proline metabolic enzymes from multiple organisms, as well as the determination of mechanisms and signal transduction pathways underlying the protective functions of proline.
Associate Professor of Biochemistry
Research focus: Structural biology, enzymology, cellular detoxification, glutathione synthesis, and salvage pathways.
- Post-doctoral Training - University of Minnesota (2002)
- Ph.D. - University of Delaware, Department of Chemistry and Biochemistry (1997)
- B.S. - University of Rochester, Biology (Biochemistry Emphasis) (1991)
Glutathione is a crucial cellular redox buffer that has been implicated in thousands of published studies on health and disease mechanisms. The pathways for its production and salvage from extracellular sources comprise a cycle that intersects with both proline and cysteine availability, in addition to the well-characterized direct roles of reduced and oxidized glutathione. However, molecular regulation of the cycle in cell and tissue specific manners is not well understood. Dr. Barycki has used a combination of structural and enzymological characterizations of the component enzymes in the cycle as well as cell culture models to obtain microarray and proteomic insights into molecular changes upon perturbation of the cycle enzymes and exposure to reactive oxygen species. Students in Dr. Barycki's laboratory solve crystal structures of glutathione biosynthetic and salvage enzymes, and provide extensive mechanistic characterizations. Current projects involve the determination of protein complex structures, characterization of enzymes in the cycle that crosstalk with those of proline metabolism, and work on enzymes of steroid inactivation and hyaluronan metabolism.
Assistant Professor of Biochemistry
Research focus: Contribution of methanogenic bacteria to gut function.
Methanogenic organisms impact agricultural biomass and mammalian gut function. Most of these organisms are strict anaerobes whose metabolic needs and impacts on the host organism are mediated through the action of unique electron transport pathways. The Buan laboratory uses methanogenic archaea as a model organism to understand responses to physiological and pathological oxidative stressors.
Professor of Chemistry
Research focus: Discovering new anti-infective agents and biosynthetic pathways from underexplored microbes.
- Postdoc. University of California, Davis
- Ph.D. The Royal Vet and Ag University, Denmark
- M.S., The Chinese Academy of Sciences
- B.S. Yunnan University, China
Novel antibiotics and other bioactive agents from microorganisms often can be produced or synthesized in large quantities at an affordable cost, so the study of underlying biosynthetic pathways for these complex, small molecule structures has the potential to advance both basic and applied research. Dr. Du's laboratory has identified small molecule products from the gliding bacteria Lysobacter species and fungal endophytes that have antibiotic, anticancer, and antifungal properties. Students in Dr. Du's laboratory are working to understand and exploit the redox-sensing biosynthetic pathways for these products so they can be engineered to function with high yields in controlled expression systems, and as paradigms for orthologous oxidative stress sensing pathways in more complex organisms.
Assistant Professor of Biochemistry
Research focus: Oma1 in mitochondrial oxidative function.
Mitochondria generate reactive oxygen species during respiration, but they are also highly sensitive to oxidative stress, buffered by specific mitochondrial protein quality control mechanisms. Research in the Khalimonchuk laboratory is focused on understanding the proteins that sense mitochondrial oxidative stress and how they regulate mitochondrial integrity. In particular, the Khalimonchuk laboratory uses yeast and mammalian cell culture models to examine inner mitochondrial membrane protein complexes sensitive to oxidative stress and the role of the oxidation-sensitive mitochondrial protease Oma1.
Susan J. Rosowski Professor of Biochemistry
Research focus: Mechanisms of cellular metal ion acquisition and detoxification and therapeutic control.
Normal cellular functions are dependent on specific metals. Because cells are sensitive to metal toxicity and metal-induced oxidative damage, the uptake, distribution, and export of metals must be tightly controlled. Dr. Lee's research focuses on understanding the function and regulation of membrane metal transporters that import or export metals such as copper, cadmium, and potassium. His lab has identified new metal transporters and shown novel modes of post-translational regulation that organisms have evolved to use inorganic elements with minimal toxicity. Students in Dr. Lee's laboratory use a combination of mouse models, mammalian cell lines, yeast genetics, and Drosophila to identify and characterize molecular factors involved in metal metabolism, determine cellular consequences of metal dyshomeostasis, and advance therapeutic control of metal metabolism.
Associate Professor of Biochemistry
Research focus: Redox regulation of DJ-1 function; structural biology.
DJ-1 is a protein implicated in a variety of diseases (e.g., prostate cancer, Parkinson's Disease) and plays an important role in the cellular defense against oxidative stress and mitochondrial damage. Cells lacking DJ-1 accumulate reactive oxygen species and die prematurely, and neuronal cells of the midbrain appear to be particularly sensitive to DJ-1 deficiency. Dr. Wilson has applied structural and biophysical approaches to examine specific molecular features that allow DJ-1 to respond to reactive oxygen species. Interestingly, he has shown that the protein initially requires an oxidation event at a conserved cysteine residue for its cytoprotective activity, and that this event regulates subsequent apoptotic signaling. Students in Dr. Wilson's laboratory are currently examining the structural elements of DJ-1 that lead to its oxidative sensing through cysteine oxidation, comparing structure and function of DJ-1 homologues from diverse organisms, and examining the molecular basis for pathogenesis of clinical DJ-1 mutants.