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 this new paradigm of "transition metal signaling" in biological models of diabetes, cardiovascular disorders, and stem cell biology, which expands the view of these elements beyond their classical roles as static enzyme cofactors.
Redox Biology, Signal Transduction, and Epigenetics
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 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 developing and applying new fluorescent, bioluminescent, magnetic resonance imaging (MRI), and positron emission tomorgraphy (PET) imaging probes for reactive oxygen, sulfur, and carbon species, as well as activity-based protein profiling (ABPP) probes, to study molecular mechanisms of oxidative and reductive signaling and stress pathways in living cells, tissue, and organisms. These chemical tools are being used to discover new sources, targets, and physiology in models ranging from neuronal networks to neural stem cell niches to cancerous tumors. A new direction for these efforts is to image changes in epigenetic signatures relating to such behaviors in real time.
Materials Biology for Solar-to-Chemical Energy Conversion
New technologies for carbon-neutral energy conversion are essential to addressing climate change and rising global energy demands. Natural photosynthesis, a process of solar-to-chemical conversion, uses light, water and carbon dioxide to generate the chemical products needed to sustain life. We are pursuing a strategy inspired by photosynthesis in which compatible inorganic and biological components are used to transform light, water, and carbon dioxide to value-added products ranging from next-generation fuels, pharmaceuticals, biodegradable materials, and sustainable food sources.
Grants from the National Institutes of Health and the Department of Energy provided partial support for these projects.
As of March 9, 2016