研究领域
Biological/Organic Chemistry/Studies of Native Proteins Using Covalent Tagging/Observation/and Perturbation
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.
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Combs-Bachmann, R.E., Johnson, J.N., Vytla, D., Hussey, A.M., Kilfoil, M.L., Chambers, J.J. Ligand-directed delivery of fluorophores to track native calcium-permeable AMPA receptors in neuronal cultures. Feb. 2015, J. Neurochemistry.
Hussey, A.M., Chambers, J.J. Methods to fluorescently label neuronal receptors for live imaging. Oct. 2014, ACS Chemical Neuroscience.
Lin, W.C., Davenport, C.M., Mourot, A., Vytla, D., Smith, C.M., Medeiros, K.A., Chambers, J.J., Kramer, R.H. Engineering a Light-Regulated GABAA Receptor for Optical Control of Neural Inhibition. ACS Chem. Biol. 2014 May 22.
Chambers, J.J. Delivery of chemical cargo to endogenous proteins on live cells. Front Chem. 2014 Mar 12;2:11. doi: 10.3389/fchem.2014.00011. eCollection 2014.
Gann, A.W., Amoroso, J.W., Einck, V.J., Rice, W.P., Chambers, J.J., Schnarr, N.A. A photoinduced, benzyne click reaction. Org Lett. 2014 Apr 4;16(7):2003-5. doi: 10.1021/ol500389t. Epub 2014 Mar 13. PMID: 24625300
Stoffolano, J.G.; Danai, L; Chambers, J.J.; Fitzpatrick, J. Factors affecting crop contraction in adult Phormia regina (Diptera: Calliphoridae). Journal of Insect Science, Jan, 2013.
McCarron, S.T.; Feliciano, M.; Johnson, J.N.; Chambers, J.J. Photoinitiated release of an aziridinium ion precursor for the temporally-controlled alkylation of nucleophiles. BMCL, 2013 Apr 15;23(8):2395-8. PMID: 23489632
Chambers, J.J. Delivery of therapeutics to the central nervous system. Advanced Drug Delivery Reviews, 2012, May 15, 64(7):589. PMID: 22388004
Vytla, D., Combs-Bachmann, R.E., Hussey, A.M., McCarron, S.T., McCarthy, D.S., Chambers, J.J. Prodrug approaches to reduce hyperexcitation in the CNS. Advanced Drug Delivery Reviews, 2012 May 15;64(7):666-85. PMID: 22138074
Vytla, D., Combs-Bachmann, R.E., Hussey, A.M., Hafez, I., Chambers, J.J. Silent, fluorescent labeling of native neuronal receptors. Org Biomol Chem. 2011 Oct 21;9(20):7151-61. Epub 2011 Sep 6. PMID: 21897969
Jackman, S.L., Babi, N., Chambers, J.J., Thoreson, W.B., Kramer, R.H. A positive feedback synapse from retinal horizontal cells to cone receptors. PLoS Biology 2011, 9(5): e1001057. doi:10.1371/journal.pbio.1001057.
Feliciano, M., Vytla, D., Medeiros, K.A., Chambers, J.J. The GABA(A) receptor as a target for photochromic molecules. Bioorg. Med. Chem. 2010, 18(22), 7731-7738.
Chambers, J.J., Kramer, R.H. Light-activated ion channels for remote control of neural activity. Meth Cell Bio. 2008, 90, 217-232.
Chambers, J.J., Banghart, M.A., Trauner, D., Kramer, R.H. Light-induced depolarization of neurons using a modified Shaker K+ channel and a molecular photoswitch. J. Neurophysiol. 2006, 96, 2792-2796.
McLean, T.H., Chambers, J.J., Parrish, J.C., Braden, M.R., Marona-Lewicka, D., Kurrasch-Orbaugh, D.M., Nichols, D.E. C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2A Receptor. J. Med. Chem. 2006, 49, 4269-4274.
Kramer, R.H., Chambers, J.J., Trauner, D. Photochemical tools for remote-control of ion channels in excitable cells. Nature Chem. Bio. 2005, 1, 360-365.
Chambers, J.J., Gouda, H., Young, D.M., Kuntz, I.D., England, P.M. Photochemically Knocking Out Glutamate Receptors in Vivo. J. Am. Chem. Soc. 2004, 126(43), 13886-13887.
Chambers, J.J., Parrish, J.C., Jensen, N.H., Kurrasch-Orbaugh, D.M., Marona-Lewicka, D., Nichols, D.E. Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands. J. Med. Chem. 2003, 46 (16), 3526-3535.
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