Howard Hughes Medical Institute Investigator and Professor of Biochemistry, Biophysics and Structural Biology*
*And of Chemistry
New molecular imaging, chemoproteomics, and optogenetics technologies for discovery and study of metal and redox signaling in neurobiology, metabolism, and cancer; materials biology for sustainable solar energy conversion
Our laboratory focuses on development of new technologies using chemical synthesis, protein engineering, and nanoscience to address specific problems of broader societal interest. Drawing from core disciplines of chemistry and molecular biology, as well as emerging fields spanning chemical biology to nanoscience, we develop new tools for molecular imaging, chemoproteomics, and optogenetics to identify and study novel chemical signals in biology, with a particular focus on neuroscience, metabolism, and cancer. Representative project areas under current investigation are summarized below.
The Chang Lab, 2015
Transition Metal Signaling. The traditional view of metals in biology is that redox-inactive alkali and alkaline metals like sodium, potassium, and calcium are broadly used for cell signaling, whereas redox-active transition metals like copper and iron are solely metabolic cofactors that must be buried and tightly-bound within protein active sites to protect the cell from potential oxidative stress and damage. Our work breaks this narrow mold by establishing a new paradigm of transition metal signaling, where these essential nutrients can also serve as dynamic cellular messengers. We are developing fluorescent, bioluminescent, and PET probes to image transition metal pools, chemoproteomics probes to identify and characterize new metalloprotein targets, and optogenetic constructs to manipulate transition metal signals in cell, tissue, and zebrafish and mouse models. These chemical tools are being applied to study the contributions of transition metal signaling to fat metabolism in obesity, diabetes, and cancer along with neural circuitry.
Metals in Neurobiology. The unique biology of the brain as the center of consciousness, from learning and memory to senses like sight, smell, and taste, is underpinned by unique chemistry that remains insufficiently understood. In particular, we are interested in understanding why the brain accumulates unexpected chemical elements at higher concentrations than any other organ or tissue, including redox-active metals like copper and iron, where at the same time these elements are misregulated in neurological disorders such as Alzheimer's and Parkinson's diseases and autism. Using CRISPR, optogenetics, high-resolution mass spec imaging, and behavioral assays, we are developing and studying new zebrafish and mouse models to explore the roles of transition metals in neural signaling and neurodegeneration.
Redox Imaging, Proteomics, and Optogenetics. 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 sulfur and carbon counterparts is much more complex, however, as emerging evidence shows that small oxygen, sulfur, and carbon metabolites, such as hydrogen peroxide, hydrogen sulfide, and formaldehyde, can mediate beneficial cellular signal transduction cascades when produced in the right place, at the right time, at appropriate levels. We are synthesizing small-molecule fluorescent, MRI, and PET imaging probes that exploit chemoselective, bioorthogonal chemistries to report on specific analytes in living cells and animals, with particular interest in the redox biology of reactive oxygen, sulfur, and carbonyl species. We are also developing new bioconjugation reactions for chemoproteomics as well as small-molecule inhibitor and antibody-drug conjugate therapeutics. Finally, we are creating optogenetic tools for controlling redox signals that govern information transfer in neural circuits in live-cell culture and mouse models.
Materials Biology for Solar Energy Conversion. Our work at the materials biology interface is inspired by natural photosynthesis, which harnesses solar energy to convert carbon dioxide and water to the value-added products needed to sustain life; however, the chemical end products are limited to biomass, a complex mixture required to make the plant's food and body. We are developing a hybrid inorganic-biological approach that can go beyond natural photosynthesis by creating cyborg cells that are capable of synthesizing a specific complex chemical product from carbon dioxide and water with sustainable solar and/or electrical input, spanning next-generation biofuels, sustainable foods, medicines, and biodegradable materials. In the longer term, this materials biology platform has the potential to endow photosynthetic capabilities to any living cell or organism.
1. “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.
2. “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.
3. "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.
4. "Copper is an endogenous modulator of neural circuit spontaneous activity", Dodani, S. C.; Firl, A.; Chan, J.; Nam, C. I.; Aron, A. T.; Onak, C. S.; Ramos-Torres, K. M.; Paek, J.; Webster, C. W.; Feller, M. B.; Chang, C. J.* Proc. Natl. Acad. Sci. USA 2014, 111, 16280-16285.
5. "Hybrid bioinorganic approach to solar-to-chemical conversion", Nichols, E. M.; Gallagher, J. J.; Liu, C.; Su, Y.; Resasco, J.; Yu, Y.; Sun, Y.; Yang, P.;* Chang, M. C. Y.;* Chang, C. J.* Proc. Natl. Acad. Sci. USA 2015, 112, 11461-11466.
6. "An Aza-Cope Reactivity-Based Fluorescent Probe for Imaging Formaldehyde in Living Cells", Brewer, T. F.; Chang, C. J.* J. Am. Chem. Soc. 2015, 37, 10886-10889.
7. "Searching for Harmony in Transition-Metal Signaling", Chang, C. J.* Nature Chem. Biol. 2015, 111, 744-747.
8. "Copper regulates cyclic-AMP-dependent lipolysis", Krishnamoorthy, L.; Cotruvo Jr., J. A.; Chan, J.; Kaluarachchi, H.; Muchenditsi, A.; Pendyala, V. S.; Jia, S.; Aron, A. T.; Ackerman, C. M.; Wander Wal, M. N.; Guan, T.; Smaga, L. P.; Farhi, S. L.; New, E. J.; Lutsenko, S.; Chang, C. J.* Nature Chem. Biol. 2016, 12, advance online publication June 6, 2016, doi: 10.1038/nchembio.2098, PMID 27272565.
Photo credit: Mark Joseph Hanson of Mark Joseph Studio.
Last Updated 2016-07-22