Project Summary/Abstract The ERK/MAPK intracellular signal transduction cascade is activated by extracellular stimuli that play important roles in nervous system development and plasticity. Genetic disruption of ERK/MAPK signaling has been implicated in neurodevelopmental syndromes, particularly the Ras/MAPK Syndromic spectrum. Yet, our understanding of the functions of this pathway in the developing brain is rudimentary. This career development proposal seeks to define the precise role of ERK/MAPK in inhibitory neural circuits that are thought to be disrupted in neurodevelopmental syndromes. During the mentored phase, we have started to define the precise functions of ERK/MAPK signaling in cortical inhibitory interneuron development (Aim 1). Definitive mouse models for conditional gain and loss of ERK/MAPK signaling have been generated and studied with advanced imaging techniques and behavioral analyses. Importantly, whether damaged inhibitory interneurons can be repaired following the normalization of aberrant ERK/MAPK activity in adult mice will be tested during the independent phase (Aim 2). Further, the global changes in gene expression that contribute to ERK/MAPK effects will be assessed specifically in inhibitory interneurons in vivo (Aim 3). Lastly, a mouse model of Noonan Syndrome, a common Ras/MAPK Syndrome, will be incorporated into the work performed in Aim 2 and 3 to further test the role of inhibitory circuitry in a germ-line model of altered ERK/MAPK signaling. These data will be essential for understanding the development and reversal of neural circuit defects in human syndromes resulting from mutations in ERK/MAPK signaling components. The long term goal will be to define mechanisms of neural circuit dysfunction and restoration in neurodevelopmental disorders, particularly those linked to ERK/MAPK dysfunction. The training acquired during the K99 phase and Dr. Sniders outstanding mentorship has been crucial in obtaining an independent faculty position. The R00 phase of this proposal will provide a key source of support to assist in establishing my laboratory.
|Effective start/end date||9/1/13 → 7/31/17|
- HHS: National Institutes of Health (NIH): $728,877.00