The research objective of this proposal is to use molecular techniques to identify novel genes involved in activity-dependent plasticity in the developing mammalian brain. Activity-dependent plasticity is manifest in a number of fundamental processes, including cortical development and synaptogenesis, learning and memory, and in neuronal repair and regeneration following injury. To achieve this long-term goal, I have formulated a training program that provides two years of didactic instruction including graduate studies in developmental neurobiology and molecular biology offered by the Departments of Neuroscience and Cellular and Molecular Biology at Johns Hopkins School of Medicine. These studies will provide a firm scientific basis for laboratory investigations that will be initiated in Phase I and be my primary focus in Phase II. Research will be conducted in the laboratory of my primary sponsor, Dr. Paul Worley. Dr. Worley, in collaboration with Dr. Daniel Nathans has developed a subtractive and differential cloning strategy using brain tissue to identify a set of (-20) novel immediate early genes (IEGs). Several clones demonstrate marked regulation during postnatal development and are strongly induced by normal synaptic activity. Because synaptic activity plays a critical role in postnatal cortical development, these genes may be important in this developmental process as well as other plastic responses. Precedent from analysis of fibroblast IEGs suggests that these brain-derived genes may represent novel transcription factors, growth factors, or cell surface molecules involved in cell-cell contacts. This proposal seeks to characterize the protein products of one or more of these neuronal IEGs. Full-length CDNAS will be isolated and sequenced, and the predicted protein sequence will be analyzed for homologies and known functional motifs. Antisera will be raised and the temporal and spatial localization of these neuronal immediate-early proteins will be determined by immunoblot and immunocytochemistry. Functional studies will be performed in order to identify the role these proteins play in the process of neural plasticity.
|Andreasson, K; Worley, P F (1995) Induction of beta-A activin expression by synaptic activity and during neocortical development. Neuroscience 69:781-96|
|Kaufmann, W E; Yamagata, K; Andreasson, K I et al. (1994) Rapid response genes as markers of cellular signaling during cortical histogenesis: their potential in understanding mental retardation. Int J Dev Neurosci 12:263-71|