Faculty and Research
Faculty by Name
Christopher Chang
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Christopher Chang
Howard Hughes Investigator and Professor of Biochemistry, Biophysics and Structural Biology*
*And of Chemistry
Research Interests
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Discovery and elucidation of new signal transduction players and pathways with molecular imaging
Our lab broadly studies the molecular roles of metals and redox-active small molecules relevant to human health, focusing on the physiology of brain, immune, and fat systems and how they are compromised in aging and disease. A general theme of our program is to discover and understand novel molecular signal transduction pathways that span a wide range of physiological and disease states through the invention and/or application of new chemical tools. Three main project areas are under current investigation.
Current Projects
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Metals in Neurobiology and Neurodegenerative Diseases. The brain offers a grand challenge for a molecular understanding of memory and senses like sight, smell, and taste, as well as developing new therapeutics for stroke, aging, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. We are particularly interested in the inorganic chemistry of the brain. Indeed, the brain requires the highest amounts of copper and iron in the human body for normal function, but levels of these redox-active metals rise and become misregulated with aging, causing uncontrolled disruptions of metal homeostasis that can lead to oxidative damage and aggregation of proteins and subsequent neuronal death. In particular, Alzheimer's and Parkinson's diseases are characterized by protein-derived plaques that accumulate unusually high amounts of abnormally distributed copper and iron compared to normal brain tissue. To study contributions of metal balance to brain function in various stages of health and disease, we are developing and applying new molecular imaging sensors and related chemical proteomics tools to interrogate, in real time, molecular aspects of cellular metal accumulation, trafficking, and redox function. We are also more broadly utilizing these reagents to discover and understand transition metal signaling in biological models of diabetes, cardiovascular disorders, and stem cell biology.
Redox Biology and Signal Transduction. The brain is the body's most oxidatively active organ, consuming more than 20 percent of the oxygen we breathe in. On the other hand, many diseases associated with aging and brain function, including cancer, diabetes, and neurodegenerative diseases such as Alzheimer's and Parkinson's, have a strong oxidative stress component stemming from cellular oxygen mismanagement. Oxidative stress is the result of unregulated production of reactive oxygen species, and accumulation of oxidative damage over time leads to the functional decline of organ systems. The biology of reactive oxygen species and their nitrogen and sulfur counterparts is much more complex, however, as emerging evidence shows that small oxygen and sulfur metabolites, such as hydrogen peroxide and hydrogen sulfide, can mediate beneficial cellular signal transduction cascades when produced in the right place, at the right time, at appropriate levels. We are developing and applying new fluorescent, magnetic resonance imaging (MRI), and positron emission tomorgraphy (PET) imaging probes for reactive oxygen and sulfur species, redox status, and enzyme activity to study molecular mechanisms of oxidative and reductive signaling and stress pathways in living cells, tissue, and organisms. The application of these new chemical tools are being used to discover new physiology in models ranging from neuronal networks to neural stem cell niches to cancerous tumors.
Metals in Immunology and Infectious Diseases. The interface between inorganic chemistry and immunology represents a rich and open area for investigation, as infectious pathogens and human hosts alike share a common need for metals such as copper, iron, and zinc for their survival, growth, and development. Because these essential nutrients cannot be synthesized but must be acquired and stored, unraveling the molecular details of this metal tug-of-war between invading microbial pathogens and potential hosts represents a significant scientific challenge. We are interested in understanding, at the molecular level, how dynamic changes in metal homeostasis pathways of the host and pathogen influence the innate immune response, pathogenicity, and virulence. Molecular imaging provides an attractive approach for studying such host-pathogen interactions in major third world infectious diseases like malaria and tuberculosis as well as in common E. coli. and Salmonella infections.
Selected Publications
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1. “Molecular Imaging of Hydrogen Peroxide Produced for Cell Signaling”, Miller, E. W.; Tulyathan, O.; Isacoff, E. Y.; Chang, C. J. Nature Chem. Biol. 2007, 3, 263-267.
2. “Aquaporin-3 Mediates Hydrogen Peroxide Uptake to Regulate Downstream Intracellular Signaling”, Miller, E. W.; Dickinson, B. C.; Chang, C. J. Proc. Natl. Acad. Sci USA 2010, 107, 15681-15686.
3. “Imaging Hydrogen Peroxide Production in Living Mice with a Chemoselective Bioluminescent Reporter”, Van de Bittner, G. C.; Dubikovskaya, E. A.; Bertozzi, C. R.; Chang, C. J. Proc. Natl. Acad. Sci USA 2010, 107, 21316-21321.
4. “Nox2 Redox Signaling Maintains Essential Cell Populations in the Brain”, Dickinson, B. C.; Peltier, J.; Stone, D.; Schaffer, D. V.; Chang, C. J. Nature Chem. Biol. 2011, 7, 106-112.
5. “Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and X-ray fluorescence microscopy”, Dodani, S. C.; Domaille, D. W.; Nam, C. I.; Miller, E. W.; Finney, L. A.; Vogt, S.; Chang, C. J. Proc. Natl. Acad. Sci. USA 2011, 108, 5980-5985.
6. "Reaction-Based Fluorescent Probes for Selective Imaging of Hydrogen Sulfide in Living Cells", Lippert, A. R.; New, E. J.; Chang, C. J. J. Am. Chem. Soc. 2011, 133, 10078-10080.
7. "Chemistry and biology of reactive oxygen species in signaling or stress responses", Dickinson, B.C.; Chang, C. J. Nature Chem. Biol. 2011, 7, 504-511.
8. "Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model", Hirayama, T.; Van de Bittner, G. C.; Gray, L. W.; Lutsenko, S.; Chang, C. J. Proc. Natl. Acad. Sci. USA 2012, 109, 2228-2233.
9. "Cell-trappable Fluorescent Probes for Endogenous Hydrogen Sulfide Signaling and Imaging H2O2-Dependent H2S Production", Lin, V. S.; Lippert, A. R.; Chang, C. J. Proc. Natl. Acad. Sci. USA 2013, 110, 7131-7135.
Last Updated 2013-06-01