SWI/SNF-REGULATED POSTNATAL ANGIOGENESIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 ATP依赖的染色质重塑复合物，如哺乳动物SWI/SNF复合物，促进基因表达的适当的时间和空间模式，因此在许多发育过程中发挥重要作用。我们以前已经证明了SWI/SNF在胚胎血管发育中的作用，现在建议将我们的研究扩展到成人。我们假设，floxed SWI/SNF催化亚基-Brg 1-将产生重要的表型时，从出生后的内皮细胞使用诱导，内皮特异性VE-钙粘蛋白-CreER转基因小鼠删除。我们建议研究出生后视网膜中的生理血管发育和肿瘤模型中的病理血管发育，重点关注与内皮BRG 1缺失胚胎的表型相似性或差异。基于我们的初步数据，我们将解决的具体假设，Wnt信号是在血管BRG 1的情况下，使用在体内和体外测定的失调。最后，我们建议确定SWI/SNF染色质重塑复合物的基因组靶点，利用复合物通过与靶基因的调控元件物理相互作用介导其表型效应的事实。我们将筛选对照细胞与突变细胞中血管生成和Wnt信号阵列以及无偏倚的全基因组阵列上代表的基因的表达变化。总之，我们提出的实验，结合我们的初步了解的作用，SWI/SNF在胚胎血管发育，站在阐明血管生成的表观遗传调控，并揭示新的介质，这一重要的发展过程。

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.