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Clockwise from top left: endothelium, astrocytes, neurons, pericytes

Brain cells types (neuronal and glial cells) have unique interactions and play critical roles in maintaining homeostasis. The pathophysiological mechanisms of most brain disorders involve complex interactions between different cell types, although certain cell types tend to be more affected than others. However, there are currently limited therapies for many neurological disorders. One potential bottleneck is the difficulty in achieving high intracellular bioavailability of pharmacological agents in the most affected cell types due to poor blood-brain barrier (BBB) permeability and lack of cellular specificity. Furthermore, pharmacological agents are generally restricted to small lipophilic molecules, significantly limiting the range of compounds for drug discovery.

Our laboratory actively focuses on understanding cellular interactions and aims to develop novel cellular-specific neurotherapeutics in the context of brain disorders. We have established innovative strategies to synthesize and screen libraries of molecules to discover novel fluorescent probes. These compounds will be carefully engineered late to serve as molecular cargoes and positron emission tomography (PET) tracers. In addition, molecular cargoes will be tested in disease mouse models to interrogate cellular specificities and pharmacological effects. During this process, we learn structure-property relationship (SPRs), structure-activity relations (SARs), and molecular mechanisms through cell-based assays and in vivo optical imaging of the mouse brain. Altogether, our efforts will provide innovative, multidisciplinary strategies for drug development that could have applications for targeting a variety of cells and brain disorders.