Research
The O’Malley laboratory is interested in the molecular and cellular bases of neurological and neuropsychiatric disorders. In particular, the lab is interested in signal transduction pathways mediated by metabotropic glutamate receptors such as mGluR5. These receptors are widely expressed throughout the CNS and play important roles modulating neuronal excitability during brain and synapse development and in learning and memory. Surprisingly, the lab found that these receptors are not only expressed on the cell surface but also on nuclear membranes where the mediate unique signaling systems associated with synaptic plasticity. Current efforts are aimed at deducing how receptors are targeted to nuclear membranes and what the long-term consequences of receptor activation are in vivo. Toward this end CRISPR techniques have been used to create transgenic animals expressing mGluR5 only on the cell surface and a separate line of animals expressing mGluR5 only on the nucleus. The plan is to use these animals to test the role of intracellular mGlu5 in vivo.
In addition, the lab has had a longstanding interest in the structure and function of dopamine receptors. The O’Malley lab was among the first to isolate D2-like genes (D2, D3, and D4) and to show their unique signaling functions. Recently, the lab has collaborated with colleagues in Psychiatry exploring associations of these genes with various neurodevelopmental disorders. In particular, variable tandem repeats in the D4 gene have been associated with ADHD, ASD, and schizophrenia (DRD4.7) versus “normal” repeat numbers (DRD4.4). Currently, the lab is testing newly created humanized DRD4.4 and DRD4.7 humanized mouse lines so as to determine differences in signaling, physiology, and behavior.
Selected publications
- Jong YJI, Harmon SK, O’Malley KL. Location and cell-type-specific bias of metabotropic glutamate receptor, mGlu5, negative allosteric modulators. ACS Chemical Neuroscience. 2019; 10(11):4558-4570.
- Sergin I, Jong YJ, Harmon SK, Kumar V, O’Malley KL. Sequences within the C terminus of the metabotropic glutamate receptor 5 (mGluR5) are responsible for inner nuclear membrane localization. J Biol Chem. 2017 Mar 3; 292(9):3637-3655.
- Vincent K, Cornea VM, Jong YJ, Laferrière A, Kumar N, Mickeviciute A, Fung JS, Bandegi P, Ribeiro-da-Silva A, O’Malley KL, Coderre TJ. Intracellular mGluR5 plays a critical role in neuropathic pain. Nat Commun. 2016 Feb 3; 7:10604.
- Purgert CA, Izumi Y, Johng YJ, Kumar V, Zorumski CF, O’Malley KL. Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus. J Neurosci. 2014 Mar 26; 34(13):4589-98.
- Kumar V, Fahey PG, Jong YJ, Ramanan N, O’Malley KL. Activation of intracellular metabotropic glutamate receptor 5 in striatal neurons leads to up-regulation of genes associated with sustained synaptic transmission including Arc/Arg3.1 protein. J Biol Chem. 2012 Feb 17; 287(8):5412-25.
- Jong YJ, Kumar V, O’Malley KL. Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signaling cascades distinct from cell surface counterparts. J Biol Chem. 2009 Dec 18; 284(51):35827-38.
See a complete list of Dr. O’Malley’s publications on PubMed.
Education
1971 BA, Honors, California State University of Sonoma
1973 MS, Biology, Portland State University (Advisors: Dr. Leonard Simpson, Univ. Oregon, Dr. Robert Terwilliger, Portland State Univ.)
1980 PhD, Biological Sciences, University of Texas in Austin (Advisor: Dr. Karl Folkers)
Selected honors
1987 Career Research Award for Women, National Science Foundation
1989-1991 Stanley Foundation Investigator, National Alliance for the Mentally Ill
1995 NARSAD Established Investigator Award
2004 Recognition for Excellence in Mentoring
2005 Outstanding Faculty Mentor Award
2006 First Annual AWN Service Award
2007 Outstanding Faculty Postdoctoral Mentor Award
2010 Distinguished Educator Postdoctoral Research Mentoring
2012 Physician and Scientist Leadership Certification
2013 Washington University School of Medicine Alumni Distinguished Faculty Award