ATP-Dependent Chromatin-Remodeling Complexes and Vascular Development

ATP依赖的染色质重塑复合物被认为在许多细胞凋亡中起重要作用。 发展过程。我们建议消除三种最著名的催化亚基， 哺乳动物染色质重塑复合物在小鼠内皮细胞，以了解其影响 对血管发育的影响我们的初步数据表明，这些配合物中至少有一类 (SWI/SNF）是正常血管发育和胚胎存活所必需的。我们亦建议 用于鉴定这些复合物的基因组靶点的策略，所述基因组靶点可能在 血管发育我们相信这些研究将阐明表观遗传学在血管内皮细胞中的作用。 形态发生，并将导致发现新的基因和信号通路参与血管 发展 该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。 发展导师的实验室提供了一个丰富的环境，学习必要的技术， 在发育中的脉管系统中发现染色质重塑复合物的靶基因。候选 将在该奖项的指导阶段在小鼠内皮细胞系中鉴定此类靶点，并将 在独立期缺乏血管染色质重塑复合物的小鼠中验证这些靶点 这个奖。此外，候选人将完善SWI/SNF缺陷的表型分析技术。 胚胎脉管系统在指导阶段的这个奖项，这将是有用的， 评估其他两类染色质重塑复合物缺乏的胚胎血管系统 在这个奖项的独立阶段。 在胚胎维管发育过程中发生的许多过程都是重演， 在成人体内形成新的血管。新血管形成可能是有益的（例如，创面 愈合）或有害（例如，在肿瘤生长过程中）。因此，该项目提供了重要的 确定基因的方法，可能导致新的疗法，以促进血管生长不足或 阻止致病性血管的生长

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.