GABA(A) RECEPTOR TRAFFICKING AND EPILEPTOGENESIS

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DESCRIPTION (provided by applicant): This proposal describes a 5-year training program to develop search career in Neuroscience. The Principal Investigator has conducted intensive and productive postdoctoral training at the University of Pennsylvania and The Children's Hospital of Philadelphia, and now is looking to expand his scientific skills by integrating his previous knowledge in cellular and molecular biology with animal models of human disease. The current proposal will explore the molecular mechanisms regulating GABAA Receptors (GABAAR) assembly and trafficking during epileptogenesis. Previous studies have demonstrated altered GABAAR subunit expression, synaptic localization and functional impairments in animal models of Temporal Lobe Epilepsy (TLE), but the molecular mechanisms triggering these changes are unknown. The proposed studies are aimed at elucidating if during epileptogenesis the interaction of GABAAR with scaffolding proteins necessary for trafficking, anchoring, and/or clustering are disrupted. Since BDNF has long been implicated in mechanisms of epileptogenesis and recently found to regulate GABAAR trafficking and expression, experiments will also be conducted to examine the role of BDNF on the regulation of protein- protein interactions, trafficking, and anchoring of GABAAR. Finally, native GABAAR multiprotein complexes will be isolated from control and epileptic rats and their components identified using a proteomic approach to generate GABAAR-associated proteomes. Once completed, this will be the first detailed analysis dealing with the regulation of GABAAR function by protein-protein interactions during epileptogenesis. These studies represent a fundamental step to elucidate the molecular components responsible for GABAAR dysregulation in epilepsy and are likely to provide new targets and novel approaches for epilepsy treatment. Dr. Amy Brooks-Kayal will act as the Primary Mentor for the scientific development of the Principal Investigator. Dr. Brooks-Kayal is a recognized leader in the study of the role of GABAAR during epileptogenesis. Dr. Brooks-Kayal is a Professor of Pediatrics at the University of Colorado and Chief of the Division of Neurology at the Children's Hospital. She has trained numerous graduate students, Postdoctoral fellows and junior faculty. Dr. Mark Dell'Acqua will be the Co-Mentor for this award. Dr. Dell'Acqua has expertise in the study of the organization of signaling complexes by anchoring proteins and synaptic plasticity, and will provide expertise to develop the trafficking and imaging studies. The University of Colorado, and in particular the Translational Epilepsy Research Program at UC Denver are an ideal setting for mentorship towards an independent scientific career, incorporating a collaborative environment that has broad faculty in the Neuroscience Program and the Departments of Pharmacology, Physiology, Pediatrics and Pharmaceutical Sciences that will maximize the potential of the Primary Investigator to develop an academic career. PUBLIC HEALTH RELEVANCE: Approximately 200,000 new cases of seizures and epilepsy occur ery ear and an estimated $15.5 billion dollars are needed to provide care for the ~3 million Americans that suffer chronic seizures or epilepsy. The most common form of epilepsy, Temporal Lobe Epilepsy, is in many cases refractory to current medications. The proposed studies aim to develop a better understanding of the molecular mechanisms that trigger epilepsy development to provide new therapeutic targets and generate novel strategies to ameliorate epilepsy progression.