Karen O’Malley, PhD

Mechanisms underlying the specification, regulation and neurodegeneration of dopaminergic and glutamatergic systems

My laboratory is interested in the molecular and cellular bases of neurological and neuropsychiatric disorders. For example, atypical dopamine function has been implicated in disorders such as Parkinson’s disease, drug addiction, affective disorders and Schizophrenia. A current lab emphasis is in determining the mechanisms of cell death in Parkinson’s disease. We are examining the biochemical and genetic events associated with parkinsonian models in vivo and in primary cultures of dopaminergic neurons. Microarray analysis is being used to globally determine which signaling pathways are utilized by parkinsonism-inducing agents as well as the known mutations. 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. In other studies, we are using homologous recombination and recombineering to create animal models in which gene expression in dopaminergic cells is spatially and temporally controlled. Our overall goal is to create an inducible animal model of Parkinson’s disease.

Another interest of the lab relates to signal transduction mediated by metabotropic glutamate receptors. Widely expressed throughout the CNS, metabotropic glutamate receptors play important roles modulating neuronal excitability during critical processes such as development, synaptic plasticity and learning. Recently we found that these receptors can be expressed on the cell surface as well as nuclear membranes where they mediate increased calcium levels. Current efforts are aimed at deducing how receptors are activated, how they are targeted to nuclear membranes, and what the long-term consequences of receptor activation are.

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