The proposed research is dedicated to the comprehensive characterization of BRF-1, a novel Ca2+-dependent transcription factor that acts within the context of the BDNF cis-regulatory apparatus. Due to its role as a transcriptional activator of BDNF, BRF-1 may be an important neuronal gene product regulating BDNF transcription in response to environmental stimuli and activity-dependent processes-issues that directly impact neuronal development, survival, and plasticity.
The aims of this proposal are the following: 1) To investigate the in vivo BRF-1 expression patterns both during development and in mature tissues, verifying that BRF-1 is spatially and temporally localized in a manner consistent with its proposed role as a regulator of BDNF gene expression; 2) To perform a detailed structural and functional analysis of the BRF-1 protein, characterizing a) the BRF-1 DNA- binding interaction and, b) specific domains critical for its function as a transcriptional activator, for the purpose of developing a dominant negative variant to block BRF-1 endogenous function; 3) To identify specific intracellular signaling pathways that target BRF-1 to modulate its activity in a Ca2+- dependent manner to control BDNF expression. Knowledge of the endogenous cellular function(s) of BRF-1 can provide new insights into the cellular control processes that govern neurotropic factor gene expression, potentially elucidating new therapeutic strategies for neurodegenerative diseases, or suggesting new approaches for neuro-regenerative therapies.
