ATP-Dependent Chromatin-Remodeling Complexes and Vascular Development

依赖于ATP的染色质重塑复合体被认为在许多 发育过程。我们建议去除三个最著名的类别的催化亚基 哺乳动物染色质重塑复合体对小鼠内皮细胞的影响 关于血管发育的研究。我们的初步数据表明，至少有一类这样的复合体 (SWI/SNF)是正常血管发育和胚胎存活所必需的。我们还提议 识别这些复合体可能调节其活性的基因组靶点的策略 血管发育。我们相信这些研究将阐明表观遗传学在血管中的作用。 形态发生，并将导致发现新的基因和信号通路涉及血管 发展。 这一奖项将推进候选人建立一个独立的血管研究实验室的目标 发展。导师的实验室为学习必要的技术提供了丰富的环境 发育中血管中染色质重塑复合体靶基因的发现。候选人 将在该奖项的指导阶段在小鼠内皮细胞系中识别这样的靶点，并将 在独立期缺乏血管染色质重塑复合体的小鼠身上验证这些靶点 这个奖项的获得者。此外，候选人将改进SWI/SNF缺陷的表型分析技术 胚胎血管在该奖项的指导阶段，这将是有用的，同时 评估另外两类染色质重塑复合体的胚胎血管缺陷 在该奖项的独立阶段。 在胚胎血管发育期间发生的许多过程在以下情况下被重述 新血管在成人体内形成。新血管的形成可以是有益的(例如，在创伤期间 在成人中)或有害的(例如，在肿瘤生长期间)。因此，该项目提供了一个重要的 定义基因的方法可以导致新的治疗方法来促进血管生长不足或 抑制致病血管生长。

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/SNFdeficient 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.