Metals in Neurobiology and Neurodegenerative Diseases
The brain offers a grand challenge for a molecular understanding of memory and senses such as sight, smell, and taste, as well as for developing new therapeutics for stroke, aging, and neurodegenerative diseases such as 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, 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, which consumes more than 20 percent of the oxygen we breathe in, is the body's most oxidatively active organ. 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. We are using these chemical tools 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 is 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 is 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 such as malaria and tuberculosis, as well as in common Escherichia coliand Salmonella infections.
Grants from the National Institutes of Health and the Department of Energy provided partial support for these projects.
As of December 11, 2012