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Richard Bridges

Regents Professor

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Personal Summary

After completing undergraduate work in Biochemistry at the University of California at Davis, Richard Bridges received a Ph.D. in Biochemistry from Cornell Medical College in 1984. Following postdoctoral and faculty positions at the University of California at Irvine, he moved to the University of Montana as an Associate Professor in 1993. He was promoted to Professor in 1998 and named Regents Professor in 2011.

Education

B.S.: University of California, Davis, (Biochemistry), 1977

Ph.D.: Cornell University Graduate School of Medical Sciences, (Biochemistry), 1984

Courses Taught

PHAR 381 Pharmaceutical Biochemistry

BIOH 441 Neurobiology of CNS Diseases

Research Interests

Research in the Bridges laboratory focuses on the transport systems responsible for mediating the uptake and sequestration of the excitatory neurotransmitter glutamate. Using conformationally constrained analogues of this acidic amino acid, Bridges and his associates probe the pharmacological specificity and the physiologically roles of these transporters in the brain and spinal cord. This work employs a wide range of experimental systems (e.g., subcellular preparations, primary tissue culture, cell lines expressing cloned transporters) and approaches (e.g., molecular modeling, organic synthesis, radiotracer flux, HPLC, radioligand autoradiography).

Elucidating how the levels of this excitatory neurotransmitter are regulated in the central nervous system is critical to understanding both glutamate-mediated neuronal signaling and glutamate-mediated neuropathology. Cellular transporters rapidly translocate extracellular glutamate into neurons and glia, potentially contributing to signal termination, the recycling of the neurotransmitter, and the maintenance of sub-pathological levels of glutamate. Another glutamate transporter, distinct from the cellular system, is present on synaptic vesicles and serves to concentrate glutamate in these vesicles prior to its release during excitatory neurotransmission.

Work in the laboratory has led to the discovery of several potent and specific inhibitors of the cellular glutamate transporters. In addition to their utility in modeling the binding sites on these proteins, these compounds have been exploited in a number of physiological preparations to investigate the consequences of impaired function. Further, considerable progress has been made in developing compounds that differentiate the processes of binding and translocation, as well exhibit selectivity among the different subclasses of cellular transporters. Recent progress has also been made in identifying a number of new inhibitors of the glutamate transporter present on synaptic vesicles. As few inhibitors have been identified for this uptake system, these compounds should be particularly valuable in investigating mechanisms underlying glutamate-mediated neurotransmission.

Other research in the group involves using conformationally constrained glutamate analogues as probes of the excitatory amino acid receptors and receptor-mediated neuronal pathology. The Bridges lab also maintains active collaborations with research groups at a number of universities including the Johns Hopkins University, University of Alabama Birmingham, and Marquette University.

Projects

New therapeutics for glioblastoma brain tumors

Brain tumors, gliomas, are among the most devastating cancers, accounting for approximately 25,000 new occurrences each year. Median survival with aggressive treatment is around 14 months, with many patients dying 6-9 months after diagnosis.  Accumulating evidence suggests that the System Xc- glutamate/cystine exchanger (Sxc-) plays a significant role in biology of gliomas and may very well represent a viable therapeutic target for drug discovery.  Recent research suggests that the peritumoral seizures exhibited by glioma patients originate from L-glutamate (L-Glu) being released by the growing tumor mass via Sxc-.  Further, L-Glu released from the tumors through Sxc- acts to destroy neurons in the vicinity, vacating room for tumors expansion, and may also serve as a signal that promotes growth and invasion.  Research conducted by the Bridges group, their collaborators, and others have identified several drug candidates that inhibit  Sxc-, attenuate peritumoral seizures, and inhibit tumor growth in vivo. Unfortuntately these candiate drugs suffer from both a lack of potency and specificty. Toward overcoming these limitations, work in our group has focused on delineating the molecualr pharmacology of Sxc- and exploiting that knowledge to develop inhibitors with greater specificity and potency.  These novel compounds are being developed in collaboration with a number of medicianl chemistry groups in our department, including those led by Drs. N. Natale, P. Diaz and C. Thompson.  In addition to increasingly potent competitive inhibitors, these studies also led to the development  of  a new first-in-class group of non-competitive inhibitors of Sxc- that act a a previously unrecognized allosteric site.  These finding provide an entirely new landscape for the development of a new generation of Sxc- inhibitors as part of our effort to develop new therapies with which to treat brain tumors.  

Newell JL, Keyari CM, McDaniel SW, Diaz PJ, Natale NR, Patel SA, Bridges RJ. Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger. Neurochem Int. 2014 Jul;73:132-8. Cited in PMCRelated citations

Sontheimer H, Bridges RJ. Sulfasalazine for brain cancer fits. Expert Opin Investig Drugs. 2012 May;21(5):575-8. . Free full textCited in PMCRelated citations

Field of Study

Neurochemistry

Molecular Pharmacology

Biochemistry

Drug Discovery

Selected Publications

Newell JL, Keyari CM, McDaniel SW, Diaz PJ, Natale NR, Patel SA, Bridges RJ. Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger. Neurochem Int. 2014 Jul;73:132-8. Cited in PMCRelated citations 

Carrigan CN, Patel SA, Cox HD, Bolstad ES, Gerdes JM, Smith WE, Bridges RJ, Thompson CM. The development of benzo- and naphtho-fused quinoline-2,4-dicarboxylic acids as vesicular glutamate transporter (VGLUT) inhibitors reveals a possible role for neuroactive steroids. Bioorg Med Chem Lett. 2014 Feb 1;24(3):850-4. 

Matti AA, Mirzaei J, Rudolph J, Smith SA, Newell JL, Patel SA, Braden MR, Bridges RJ, Natale NR. Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5931-5. .Free full textRelated citations

Bridges R, Lutgen V, Lobner D, Baker DA. Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev. 2012 Jul;64(3):780-802.  Free full textCited in PMCRelated citations

Cardozo-Pelaez F, Bridges RJ. Coupling biomarkers and drug action for neurodegenerative disease therapies: does the nose know?: Commentary on Sattler et al.: human nasal olfactory epithelium as a dynamic marker for CNS therapy development. Exp Neurol. 2012 Jun;235(2):508-12.  Related citations

Sontheimer H, Bridges RJ. Sulfasalazine for brain cancer fits. Expert Opin Investig Drugs. 2012 May;21(5):575-8. . Free full textCited in PMCRelated citations

Bridges RJ, Natale NR, Patel SA. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012 Jan;165(1):20-34. Free full textCited in PMCRelated citations

Pathmajeyan MS, Patel SA, Carroll JA, Seib T, Striebel JF, Bridges RJ, Chesebro B. Increased excitatory amino acid transport into murine prion protein knockout astrocytes cultured in vitro. Glia. 2011 Nov;59(11):1684-94.  Free full textCited in PMCRelated citations

Seib TM, Patel SA, Bridges RJ. Regulation of the system x(C)- cystine/glutamate exchanger by intracellular glutathione levels in rat astrocyte primary cultures. Glia. 2011 Oct;59(10):1387-401.  Cited in PMCRelated citations

Ahmed SK, Etoga JL, Patel SA, Bridges RJ, Thompson CM. Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-). Bioorg Med Chem Lett. 2011 Jul 15;21(14):4358-62.   Free full textCited in PMCRelated citations

Etoga JL, Ahmed SK, Patel S, Bridges RJ, Thompson CM. Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system x(c)(-) over the vesicular glutamate transporter. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2680-3.  Free full textCited in PMCRelated citations

Patel SA, Rajale T, O'Brien E, Burkhart DJ, Nelson JK, Twamley B, Blumenfeld A, Szabon-Watola MI, Gerdes JM, Bridges RJ, Natale NR. Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model. Bioorg Med Chem. 2010 Jan 1;18(1):202-13.  Free full textCited in PMCRelated citations

 

Affiliations

         Research Centers                               Graduate Programs                           Professional Organizations

Center for Structural &                              Pharmaceutical Sciences                             Society for Neuroscience

       Functional Neuroscience                   Neuroscience

Center for Biomolecular                            Chemistry & Biochemistry

       Structure & Dynamics                        Biology