ATP-dependent chromatin-remodeling complexes are thought to play important roles in a number of developmental processes. We propose to ablate the catalytic subunits of the three best-known classes of mammalian chromatin-remodeling complexes in mouse endothelium in order to understand their influence on vascular development. Our preliminary data indicate that at least one class of these complexes (SWI/SNF) is necessary for normal vascular development and for embryonic viability. We also propose strategies for identifying genomic targets of these complexes that might mediate their activities during vascular development. We believe these studies will clarify the role of epigenetics in vascular morphogenesis and will lead to the discovery of new genes and signaling pathways involved in vascular development. This Award will advance the candidate's goal of establishing an independent lab for the study of vascular development. The mentor's lab provides a rich environment for learning techniques necessary for the discovery of target genes of chromatin-remodeling complexes in the developing vasculature. The candidate will identify such targets in a mouse endothelial cell line during the mentored phase of the Award and will verify those targets in mice lacking vascular chromatin-remodeling complexes during the independent phase of this Award. Additionally, the candidate will refine techniques for the phenotypic analysis of SWI/SNF- deficient embryonic vasculature during the mentored phase of this Award, which will be useful while evaluating embryonic vasculature deficient for the two other classes of chromatin-remodeling complexes during the independent phase of this Award. Many of the processes that occur during vascular development in the embryo are recapitulated when new blood vessels are formed in the adult. New vessel formation can be beneficial (e.g., during wound healing) or detrimental (e.g., during tumor growth) in the adult. Therefore, this project provides an important approach to defining genes that could lead to novel therapies to promote insufficient vascular growth or to disable pathogenic vascular growth.
| Ingram, Kyle G; Curtis, Carol D; Silasi-Mansat, Robert et al. (2013) The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis. PLoS Genet 9:e1004031 |
| Griffin, Courtney T; Curtis, Carol D; Davis, Reema B et al. (2011) The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels. Proc Natl Acad Sci U S A 108:2282-7 |
| Griffin, Courtney T; Brennan, Jennifer; Magnuson, Terry (2008) The chromatin-remodeling enzyme BRG1 plays an essential role in primitive erythropoiesis and vascular development. Development 135:493-500 |
