This K08 Mentored Clinician-Scientist Career Development Award application, entitled NMDA Receptor Trafficking by the Autophagy Regulatory Protein Beclin 1, is submitted by Edward D. Plowey, M.D., Ph.D., Assistant Professor of Pathology at Stanford University School of Medicine. Dr. Plowey is a neuropathologist and clinician-scientist whose research interests lie in neurodegeneration and the mechanisms through which synapses and neurons cope with or succumb to neurodegenerative disease stressors. Dr. Plowey's immediate research goal is to investigate novel roles for autophagy in mediating adaptive synaptic adjustments to neurodegenerative disease stressors as the cornerstone of his independent research program. In this research proposal, a focus on beclin-dependent autophagy as a novel mechanism to regulate synaptic versus extra synaptic localization, subtype, internalization and degradation of NMDA receptors is proposed. He will test his hypothesis that beclin-dependent autophagy mediates neuroprotective modulation of NMDA receptor pools.
In Aim 1 of this research proposal, the effects of synaptic versus extra synaptic NMDA receptor activation on beclin 1 levels, BECN1 gene expression and the capacity for neuroprotective beclin-dependent autophagy will be investigated. In the second Aim, the impact of beclin-deficiency on surface NMDA receptor levels, localization, subtype distribution and toxicity will be delineated.
In Aim 3, the molecular basis, trafficking effects and modulatory effects of APP on beclin 1 interactions with NMDA receptors will be investigated, with a focus on the possibility that beclin 1 targets surface NR1/NR2B receptors for autophagolysosomal degradation by incorporation into plasma membrane derived autophagosomal precursor vesicles. Dr. Plowey will learn how autophagy modulates neuronal protein turnover and excitability secondary to synaptic perturbations and how beclin-dependent autophagy impacts NMDA receptor trafficking and the balance of synaptic and extra synaptic NMDA receptors. Furthermore, he will broaden our knowledge of the potential for beclin-dependent autophagy as a therapeutic target in neurodegeneration. Dr. Plowey's career development plan includes advanced research training in synaptic neurobiology techniques including receptor trafficking studies, patch clamp electrophysiology, organotypic slice cultures, subcellular fractionation approaches, molecular interaction studies and approaches to study the localization and functional outputs of synaptic and extra synaptic NMDA receptors. He will also engage in training activities to improve his grant writing and manuscript writing skills and increase his professional network and visibility in the scientific community through professional service, workshops and conferences. The collegial academic environment at Stanford University is ideal for the successful career development of clinician-scientists. Dr. Plowey has strong institutional commitment to his career development as an independent clinician-scientist from the Department of Pathology at Stanford University School of Medicine, which includes commitment of laboratory space, generous laboratory startup funds and 75% protected time to devote to his research program and career development activities. Furthermore, Dr. Plowey has established ideal mentor-prot?g? relationships with productive senior investigators with extensive mentorship experience in Tony Wyss-Coray, Ph.D. and Craig Garner, Ph.D. With a K08 Career Development Award to support his research and career development plans, Dr. Plowey will be positioned for success in his long term goals as a practicing neuropathologist and as a principal investigator of a sustainable NIH R01 funded research program in the synaptic neurobiology of neurodegeneration.
Neurodegenerative diseases, including Alzheimer's disease, contribute a large burden of suffering and costly medical care to the elderly as they deprive their victims of cognitive function, movement and essential activities of daily living. While we are beginning to understand some of the root causes of these diseases and how they destroy important brain connections called synapses, we have a long way to go to translate our knowledge into strategies to improve public health. This goal of this project and training program is to support the Principal Investigator in the establishment of an independent research program to investigate how synapses cope or succumb to neurodegenerative disease processes and to leverage the resulting knowledge into novel and effective disease treatments.
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