Principal Research Interests - 

Applying novel chemical biology tools and emerging biophysical techniques to solve
fundemental questions in neuroscience is the focus of my research. This includes receptor
trafficking and ligand-gating, remote control of neuronal activity with chemicals and
light, and computer modeling of ligand recognition by biological receptors. 

Real-Time Protein Tracking: One of the main problems confronting neuroscience is a lack
of understanding of the daily lives of membrane receptors. To study protein localization
and dynamics, it is common to label a protein with a fluorescent tag or other contrast
agent and track their motion with optical microscopy. The main strategies used for
labeling are overexpression of a fusion protein and antibody-based labeling. These two
methods, however, may lead to confounds based on disruption of native subunit composition
or alteration of the activity of the target, respectively. Our receptor tagging method
utilizes low molecular weight nanoprobes that can be remotely deployed to target specific
receptors. The initial target for this project will be the subtype of the glutamate
receptor called the AMPA receptor. 

Using Light and Chemistry to Affect Cellular Function: Various strategies have been
devised for imparting light-sensitivity onto normally light-insensitive cells to remotely
control their excitability. Coupling specifically substituted photochromic molecules with
endogenous proteins has been successfully used to affect the activity of living cells.
Light can be used to reversibly isomerize the attached photochromic molecule causing
activation or inactivation of single cells or at specific locations on a cell, such as
dendritic branches or even individual spines. In addition to using this current method,
we will expand the toolbox for cell control using light. Novel chemical tools that allow
control of neuronal function using only chemicals and light will be a research area of
tremendous wealth in the next decade. 

Exploration of Small Molecule Binding Sites: The family of G-Protein-coupled receptors
represents a large target for disease treatment as well as for a basic understanding of
neuroscience. By using computational chemistry methods we plan to investigate further
both the ligand binding sites and, more interestingly, activation mechanisms of members
of the amine-binding GPCR family. We also have an interest in using this model in
conjunction with library virtual screening to de-orphan orphan receptors.

No subject area

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Silent, fluorescent labeling of native neuronal receptors (with D Vytla, R E. Combs-Bachmann, A M. Hussey, and I Hafez), Organic & Biomolecular Chemistry (2011)

We have developed a minimally-perturbing strategy that enables labeling and subcellular visualization of endogenous dendritic...

 

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A Positive Feedback Synapse from Retinal Horizontal Cells to Cone Photoreceptors (with Skylar L. Jackman, Norbert Babai, Wallace B. Thoreson, and Richard H. Kramer), PLoS Biology (2011)

Cone photoreceptors and horizontal cells (HCs) have a reciprocal synapse that underlies lateral inhibition and...

 

The GABA(A) receptor as a target for photochromic molecules (with M. Feliciano, D. Vytla, and K. A. Medeiros), Bioorganic & Medicinal Chemistry Letters (2010)

Photochromic ligands, molecules that can be induced to change their physical properties through applied light,...