Bryan Roth, PhD, MD

Bryan Roth, PhD, MD
  • Director, NIMH Psychoactive Drug Screening Program
  • Professor
  • Other
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Bryan Roth, PhD, MD

Research Synopsis

The Roth Lab studies the structure and function of G-Protein coupled receptors (GPCRs). For more specific information, check out the lab's research page. The Roth lab is the principal contractor for the NIMH Psychoactive Drug Screening Program, which includes the PDSP Ki database.

Profile

Bryan Roth, PhD, MD is a professor in the Division of Medicinal Chemistry and Natural Products and in the Department of Pharmacology. He is also the director of the NIMH Psychoactive Drug Screening Program.

The Roth lab focuses on the following areas of research:

Chemical-Genetics

The Roth lab has pioneered the use of directed molecular evolution to create GPCRs that are suitable for remotely controlling cellular signaling. Using a variety of mouse genetic approaches (e.g. Cre-mediated recombination; Tet-inducible systems; BAC-transgenic), the lab is able to control neuronal firing and non-neuronal signaling in real-time in awake, freely moving animals (see Armbruster et al, PNAS 2007; Conklin et al, Nature Methods, 2008; Alexander et al, Neuron 2009; Guettier et al, PNAS 2009; Dong et al, Nature Protocols 2010). This technology has afforded the scientific community the opportunity to discover how cell-type specific modulation of signaling is translated into behavioral and non-behavioral outcomes. Ongoing projects are to use this technology to deconstruct the neuronal requirements for simple and complex behaviors, particularly as they relate to schizophrenia and drug abuse.

Chemical Biology and the Receptorome

The Roth lab has pioneered the approach of massively-parallel physical screening of the GPCR-ome. The lab’s approach differs in that the lab screens, in a parallel fashion, entire families of receptors simultaneously to discover molecular targets of biologically important molecules (peptides, drugs, natural products). This work is facilitated by the NIMH Psychoactive Drug Screening Program, which is housed in the Roth lab. Using this approach, the lab has:

  1. Discovered the Κ-opioid receptor as the sole molecular target of salvinorin A-the active ingredient of the natural hallucinogen Salvia divinorum (Roth et al, PNAS, 2002). Ongoing projects are to discover the molecular and neurobiological underpinnings of salvinorin A's hallucinogenic actions.
  2. Discovered the 5-HT2B receptor as being responsible for drug-induced valvular heart disease (Roth, NEJM, 2007). Ongoing projects are to exploit serotonin receptor pharmacology for psychiatric and obesity-related drug discovery efforts.
  3. Used this platform, working together with Brian Shoichet's lab at UCSF, for the near duggable-genome-wide discovery of new molecular targets for approved drugs (Keiser et al, Nature, 2009;Keiser et al, Nature Biotech 2007). Ongoing projects are focused on using this technology to de-orphanize the remaining orphan GPCRs in the genome (~150) and to uncover the hidden pharmacology of known medications.

Serotonin receptor neurobiology

Since 1984, the Roth lab has studied serotonin (5-hydroxytryptamine; 5-HT) and its receptors. Recently the lab has been focused on targeting and trafficking of 5-HT2-family receptors (Elphick et al, Science, 2004; Scheffler et al, PNAS 2006; Abbas et al, J Neurosci 2009;Magalhaes et al,Nature Neurosci, 2010). Ongoing projects are directed to using mouse genetics to delineate the roles of accessory proteins and post-translational modifications in 5-HT receptor actions.

 

Most Recent Publications

1. Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KL, Edwards DD, Shoichet BK, Roth BL. Predicting new molecular targets for known drugs.  Nature. 2009 Nov 12;462(7270):175-81

2. Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton JW, Lee HM, Chen X, Jin J, Bridges AS, Zylka MJ, Roth BL, Philpot BD. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons..   Nature. 2011 Dec 21.

3. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry.  Nat Biotechnol. 2007 Feb;25(2):197-206

4. Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK. Ligand discovery from a dopamine D(3) receptor homology model and crystal structure.  Nat Chem Biol. 2011 Sep 18;7(11):769-78. doi: 10.1038/nchembio.662

5. Laggner C, Kokel D, Setola V, Tolia A, Lin H, Irwin JJ, Keiser MJ, Cheung CY, Minor DL, Jr., Roth BL, Peterson RT, Shoichet BK. Chemical informatics and target identification in a zebrafish phenotypic screen..  Nature Chem Biol. 2011 Dec 18.

6. Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells..  Nature Chem Biol. 2011 Aug;7(8):566-74.

7. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, Guettier JM, Chang WC, Pei Y, McCarthy KD, Nissenson RA, Wess J, Bockaert J, Roth BL. Engineering GPCR signaling pathways with RASSLs.  Nat Methods. 2008 Aug;5(8):673-8

8. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J.
Nat Chem Biol. 2011 Aug 17;7(9):648. doi: 10.1038/nchembio0911-648c. No abstract available.
PMID: 21850000 [PubMed - in process]

9. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J.
Nat Chem Biol. 2011 Jul 10;7(8):566-74. doi: 10.1038/nchembio.599.
PMID: 21743462 [PubMed - in process]

10. ANTAGONIST FUNCTIONAL SELECTIVITY: 5-HT2A SEROTONIN RECEPTOR ANTAGONISTS DIFFERENTIALLY REGULATE 5-HT2A RECEPTOR PROTEIN LEVEL IN VIVO. Yadav PN, Kroeze W, Farrell M, Roth BL. J Pharmacol Exp Ther. 2011 Jul 7. [Epub ahead of print] PMID: 21737536 [PubMed - as supplied by publisher]

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