This proposal focuses on biochemical, molecular, and cellular aspects of endocrinology, especially as it relates to Vitamin A signaling. The major hypothesis of this proposal is that transcriptional regulation by retinoids is mediated through distinct coactivator and corepressor complexes that interact with nuclear receptors in a hormone-dependent fashion. Consistent with the notion that enzymatic activities may be required to regulate target gene expression, the nuclear receptor corepressors SMRT and N-CoR associate with Sin3A which in turn binds class I histone deacetylases (HDACs) enabling the formation of a multimeric HDAC complex. Reciprocally, many of the nuclear receptor coactivators identified, including ACTR and SRC-1, exhibit histone acetyltransferase (HAT) activities. The goal of Specific Aim 1 is to define the molecular basis for corepressor recognition of non-liganded receptors and to establish the basis for receptor subtype specificity.
This aim will employ biochemical and molecular approaches to study the interaction between RAR and its corepressor SMRT.
In Specific Aim 2, the investigator will characterize corepressor associated proteins by """"""""purifying the nuclear screens"""""""" (typo in the abstract, presumably meant purification and two-hybrid screens).
Specific Aim 3 will determine the role of corepressor proteins in chromatin remodeling. These studies will systematically investigate the role of receptor-dependent repression of target genes prior to hormonal stimulation.
Specific Aim 4 will investigate the role of RAR and RXR mutant mice in hippocampal-based spatial learning and memory. The investigator will also use cDNA array analysis and a number of RNA cataloguing techniques to identify changes in mRNA populations associated with F9 and P19 cell differentiation.
Aim 5 is to establish an """"""""in vivo"""""""" (from abstract, presumably meant """"""""in vitro"""""""") transcription system reconstituted with chromatin templates for the functional analysis of individual purified cofactors. Together these studies will provide valuable new insight into the biochemical and molecular mechanisms that underlie broad aspects of endocrine physiology and human disease.
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