ATP-Dependent Chromatin-Remodeling Complexes and Vascular Development

ATP 依赖性染色质重塑复合物和血管发育

基本信息

批准号：
7651867
负责人：
Courtney T Griffin
金额：
$ 24.9万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7651867
关键词：
ATP phosphohydrolase Ablation Adult Alleles Animals Apoptosis Award Binding Biological Assay Blood Blood Vessels Breeding Candidate Disease Gene Catalytic Domain Cell Line Cessation of life Chromatin Chromatin Remodeling Factor Class Complex DNA DNA Repair Data Defect Detection Development Developmental Process Electron Microscopy Embryo Embryonic Development Endothelial Cells Endothelium Environment Epigenetic Process Eukaryota Eukaryotic Cell Gene Expression Gene Targeting Generations Genes Genetic Transcription Genomics Glean Goals Growth Hematopoietic Histology Histones ISWI Lead Learning Mediating Mediator of activation protein Mentors Microarray Analysis Molecular Molecular Conformation Morphogenesis Mus Mutation NuRD complex Nuclear Nucleosomes Numbers Pattern Phase Phenotype Play Positioning Attribute Process Reporter Role SMARCA4 gene SMARCA5 gene Signaling Pathway Gene Techniques Testing Thinking Time Transcriptional Regulation Transgenic Organisms Vascular Endothelium Wound Healing Yolk Sac genetic analysis in vitro Assay knock-down member mutant novel promoter retinal rods tumor growth vector

项目摘要

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.

依赖ATP的染色质复制复合物被认为在许多人中起着重要作用发展过程。我们建议消除三个最著名类别的催化亚基小鼠内皮中的哺乳动物染色质复合物复合物，以了解其影响关于血管发育。我们的初步数据表明，至少一类这些复合物（SWI/SNF）对于正常的血管发育和胚胎生存力是必需的。我们也建议识别这些复合物的基因组靶标的策略血管发展。我们认为这些研究将阐明表观遗传学在血管中的作用形态发生，并将导致发现新基因和血管中涉及的信号通路发展。该奖项将促进候选人建立一个独立实验室研究的目标发展。导师实验室为学习技术提供了丰富的环境在发育中的脉管系统中发现染色质复制复合物的靶基因。候选人将在奖励的指导阶段中识别鼠标内皮细胞系中的此类目标，并将验证在独立阶段缺乏血管染色质复合物复合物的小鼠中的那些靶标这个奖项。此外，候选人将完善用于SWI/SNFDEEDICER的表型分析的技术在该奖项的指导阶段，胚胎脉管系统将很有用评估其他两个类别的染色质复合物复合物缺乏胚胎脉管系统在本奖项的独立阶段。当胚胎中血管发育期间发生的许多过程被概括成人形成新的血管。新容器的形成可能是有益的（例如，在伤口期间成人的愈合）或有害（例如在肿瘤生长期间）。因此，该项目提供了重要的定义可能导致新疗法以促进血管生长不足或禁用致病性血管生长。