This grant is a request for a NINDS Career Development Award for Minority Scholars in Neuroscience (K01) to investigate the Regulation of NMDA Receptor Trafficking by Dopamine. Interactions between the dopaminergic and glutamatergic systems in the striatum have implications for the pathogenesis and treatment of Parkinson's disease. My previous work has revealed significant modifications in the properties of striatal NMDA glutamate receptors in animal models of Parkinson's disease. Intriguingly, the alterations in striatal NMDA receptors occur at the level of assembly, phosphorylation and synaptic localization of the subunit proteins, and involved redistribution of receptors between sub-cellular compartments. Furthermore, we recently reported evidence for a rapid dopamine D1 receptor dependent mechanism for the trafficking of striatal NMDA receptors from intracellular compartments to the post-synaptic membrane. The molecular mechanisms for the dopamine D1 receptor mediated sub-cellular trafficking of NMDA receptors in the striatum remain largely unknown. Therefore, I will apply my molecular neuroscience and neuropharmacology backgrounds to experimentally explore and unravel the dopamine receptor dependent molecular mechanisms and signaling pathways underlying the trafficking of striatal NMDA glutamate receptors to brain synapses in primary cell culture system. As a research fellow, I have gained knowledge and received proper training in molecular mechanisms of dopamine and glutamate mediated signal transduction pathways in both in vivo and in vitro systems. The proposed career development program will further my understanding of how the dopamine and glutamate systems in the striatum interact and lead to the pathogenesis of Parkinson's disease. This career development program along with my assembled team of scientists will continue to contribute to my professional and intellectual growth, and eventually establish myself as an independent investigator. The findings from this research proposal may ultimately lead to the development of new therapeutic options for human Parkinson's disease.
|Ayala, Ramses; Kett, Lauren R; Leach, Tiffany L et al. (2012) Metabotropic glutamate receptor 1 (mGluR1): antibody specificity and receptor expression in cultured primary neurons. J Neurosci Methods 204:221-6|
|Orlando, Lianna R; Ayala, Ramses; Kett, Lauren R et al. (2009) Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5. J Neurochem 110:557-69|
|Hallett, Penelope J; Spoelgen, Robert; Hyman, Bradley T et al. (2006) Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J Neurosci 26:4690-700|