(DBBS Faculty Member)
Anatomy and Neurobiology
My laboratory is interested in the molecular and cellular bases of neurological and neuropsychiatric disorders. For example, atypical dopamine function has been implicated in clinical disorders such as Parkinsonís Disease, drug addiction, affective disorders and Schizophrenia. Currently we are using the specificity inherent in the dopaminergic biosynthetic enzyme, tyrosine hydroxylase, to create transgenic animal models in which gene expression is spatially and temporally controlled. Such animals will serve as an invaluable resource for turning gene expression on and off in catecholaminergic cells.To date, we have made significant progress in defining dopaminergic response elements associated with the tyrosine hydroxylase gene. For example, the successful targeting of human Bcl-2 to midbrain dopaminergic neurons has allowed us to test hypotheses regarding the role of this anti-apoptotic protein in protecting cells from parkinsonian toxins. Currently, we are focusing on an inducible animal model of Parkinsonís Disease.
Another project attempts to extend this analysis by determining the mechanisms of cell death in this disorder. Several drugs have been shown to mimic Parkinsonís Disease in animals. We are examining the biochemical and genetic events associated with these drugs in primary cultures of dopaminergic neurons. Results from these studies have suggested distinct pathways of cell death can be triggered in these neurons. To further address these differences, microarray analysis is being used to globally determine which signaling pathways are utilized by parkinsonism-inducing agents as well as the known mutations, alpha synuclein and parkin. Enhanced understanding of the common and distinct cell death mechanisms associated with these toxins and genes may identify unique cellular targets for the generation of novel therapeutic interventions.
Kim-Han JS, Antenor-Dorsey JA, O'Malley KL (2011 May 11). The Parkinsonian Mimetic, MPP+, Specifically Impairs Mitochondrial Transport in Dopamine Axons. J Neurosci. 31 (19): 7212-21. Full Article >
Jong YJ, Kumar V, O'Malley KL (2009 Dec 18). Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signaling cascades distinct from cell surface counterparts. J Biol Chem. 284 (51): 35827-38. Full Article >
Bernstein AI, Garrison SP, Zambetti GP and O'Malley KL (2010) 6-OHDA generated ROS induces DNA damage and p53- and PUMA-dependent cell death. Mol. Neurodegeneration (In Press)
Brown JA, Emnett RJ, White CR, Yuede CM, Conyers SB, O'Malley KL, Wozniak DF, Gutmann DH (2010 Nov 15). Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice. Hum Mol Genet. 19 (22): 4515-28. Full Article >
Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O'Malley K, Salkoff L (2009 Jun). Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci. 12 (6): 745-50. Full Article >
Kumar V, Jong YJ, O'Malley KL (2008 May 16). Activated nuclear metabotropic glutamate receptor mGlu5 couples to nuclear Gq/11 proteins to generate inositol 1,4,5-trisphosphate-mediated nuclear Ca2+ release. J Biol Chem. 283 (20): 14072-83. Full Article >
Karen O'Malley, Ph.D
Office Location: 913 McDonnell Sciences Bldg.
Office Phone: 314-362-7087
Lab Phone: 314-362-7090
Campus Box: 8108