Chemical Probes to Study Metal Biology

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Project Summary/Abstract Copper is an essential metal nutrient that plays important roles in human health and disease. The potent redox activity of copper is required for a diverse array of physiological processes including respiration, antioxidant defense, neurotransmitter synthesis, and wound healing. However, dysregulated copper homeostasis can contribute to metabolic diseases like obesity and diabetes as well as cancer, heart disease, and neurodegenerative disorders, often through aberrant oxidative stress and damage pathways. To help decipher the contributions of copper to healthy and disease states, we are developing new chemical tools to enable copper-specific imaging in living systems across a broad range of biological models, from subcellular compartments to cells to whole animals. The scientific premise is that building a copper imaging toolkit will provide foundational chemical reagents to further our understanding of the roles of copper in both physiological and pathological situations. This competitive renewal application is driven by design innovations where we invent new generalizable, activity-based sensing platforms for copper detection, as well as scientific rigor in the synthesis and use of multiple characterization techniques to apply these tools in cell and animal models. Specifically, we will pursue protein-labeled copper probes to study how copper is stored, trafficked, and utilized at the subcellular level, chemiluminescent indicators to enable dynamic and longitudinal copper imaging at the live animal level, and studies to probe how copper contributes to managing oxidative stress in neuronal cultures and regulating neural circuitry and behavior in zebrafish models.