Advancing our understanding of neuroplasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of nervous system disorders. Recent molecular, cellular, and behavioral findings have revealed the importance of epigenetic mechanisms that alter chromatin structure in maintaining stable patterns of gene expression and altering neuroplasticity associated with mood and memory formation. However, the dynamic and combinatorial nature of these signaling events has meant that the state of our understanding and ability to manipulate the underlying molecular mechanisms in the nervous system remains limited. To overcome these limitations, the long-term goals of the studies outlined in this proposal are to systematically develop selective, brain-penetrant, small-molecule probes (SMPs) of chromatin-remodeling complexes that affect neural activity-regulated gene transcription. Our overall hypothesis is that by selectively targeting the enzymatic activity of specific members of the histone deacetylase (HDAC) and histone acetyltransferase (HAT) families that it will be possible manipulate the acetylation state of histones in the promoters of certain immediate early genes (IEGs) thereby affecting neural- activity-regulated gene transcription and neuroplasticity. To develop the methods and SMPs necessary to rigorously test this hypothesis the proposed studies will address the following aims.
In Aim I, the structure- activity-relationships of two types of SMPs that enhance cAMP response element (CRE)-mediated transcription through affecting the activity of certain HDAC and HAT isoforms will be determined. As a sub-aim, proteomic profiling using affinity probes will be used to determine the components of the chromatin-remodeling complexes targeted by both types of SMPs.
In Aim II, a real time, automated microscopy-based imaging assay of cultured neurons from bacterial artificial chromosome (BAC)-transgenic mice expressing a genetically encoded fluorescent reporter of IEG expression, will be developed. As a sub-aim, this assay will be used in combination with immunofluorescent detection of histone-modifications to characterize the effect of manipulating HDAC/HAT-complex activities on IEG expression using SMPs and RNAi-mediated gene silencing.
In Aim III, the effect of specific HDAC inhibitors and HAT activators in mouse behavioral tests of hippocampal-dependent memory and depression-like behavior will be determined along with measurements of corresponding changes in brain gene expression patterns and histone acetylation. Significance: We anticipate these multidisciplinary studies will shed new light on molecular mechanisms of neuroplasticity and the relevance of these mechanisms to the development of novel therapeutics for memory and mood disorders.
Advancing our understanding of brain plasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of a myriad of central nervous system disorders. This work will characterize the role that gene expression plains in mediating aspects of brain plasticity relevant to mood and memory disorders using small molecules as probes in biochemical and mouse behavioral studies. These multidisciplinary studies will shed new light on molecular mechanisms of brain plasticity and the relevance of these mechanisms to the development of novel therapeutics for their treatment of memory and mood disorders.
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