This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ATP-dependent chromatin-remodeling complexes, such as the mammalian SWI/SNF complexes, facilitate proper temporal and spatial patterns of gene expression and therefore play important roles in a number of developmental processes. We have previously demonstrated a role for SWI/SNF in embryonic vascular development and are now proposing to extend our studies into the adult. We hypothesize that the floxed SWI/SNF catalytic subunit--Brg1--will yield important phenotypes when deleted from postnatal endothelium using inducible, endothelial-specific VE-Cadherin-CreER transgenic mice. We propose to investigate both physiological vascular development in the postnatal retina and pathological vascular development in a tumor model, focusing on phenotypic similarities or differences with embryos depleted of endothelial BRG1. Based on our preliminary data, we will address the specific hypothesis that Wnt signaling is misregulated in the absence of vascular BRG1 using both in vivo and in vitro assays. Finally, we propose to identify genomic targets of SWI/SNF chromatin-remodeling complexes by taking advantage of the fact that the complexes mediate their phenotypic effects by physically interacting with regulatory elements of target genes. We will screen control versus mutant cells for expression changes in genes represented on angiogenesis and Wnt signaling arrays as well as unbiased whole-genome arrays. Altogether, our proposed experiments, in combination with our preliminary understanding of the role of SWI/SNF in embryonic vascular development, stand to elucidate the epigenetic regulation of angiogenesis and to reveal novel mediators of this important developmental process.
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