Regulation of Venous and Lymphatic Identity by Chromatin-Remodeling

通过染色质重塑调节静脉和淋巴特性

• 批准号: 8857150
• 负责人: Courtney T Griffin
• 金额: $ 41.37万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857150
• 关键词: Address; Affect; Blood; Blood Vessels; Chromatin Remodeling Factor; Data; Defect; Development; Developmental Process; Embryo; Embryonic Development; Endothelial Cells; Enzymes; Epigenetic Process; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Histone Acetylation; Human; Laboratories; Location; Lymphatic; Lymphatic Diseases; Lymphatic vessel; Maintenance; Mediating; Mission; Mus; Mutant Strains Mice; Nuclear Orphan Receptor; Nuclear Receptors; Nucleosomes; Pathology; Phenocopy; Phenotype; Play; Public Health; Regulation; Research; Research Support; Role; SMARCA4 gene; Testing; Time; Transcriptional Regulation; Veins; Venous; Work; apoAI regulatory protein-1; base; chromatin remodeling; disability; epigenetic regulation; improved; innovation; mutant; novel; novel strategies; postnatal; promoter; tool; tumor

DESCRIPTION (provided by applicant): Epigenetic regulators play important roles in a variety of developmental processes, but little is understood about how they modulate vascular specification. A long-term goal of the applicant's laboratory is to understand how ATP-dependent chromatin-remodeling complexes epigenetically regulate transcription of genes that con- tribute to developmental and postnatal vascular pathologies, such as those that arise from misspecification of blood and lymphatic vessels. The objective of this proposal is to understand how the chromatin-remodeling enzymes BRG1 and CHD4 influence venous and lymphatic identity during embryonic development. The cen- tral hypothesis is that BRG1 and CHD4 affect venous and lymphatic identity by modulating vascular expression of the nuclear receptor Coup-TFII. This hypothesis is based on preliminary data produced in the applicant's laboratory and on phenotypic similarities between vascular Brg1, Chd4, and Coup-TFII mutant mouse em- bryos. Coup-TFII plays important roles in venous and lymphatic specification but nothing is known about what promotes its vascular expression. Therefore identification of epigenetic mechanisms for regulating its expres- sion would elucidate how COUP-TFII influences vessel development. Two specific aims will be employed to test the central hypothesis. First, the temporal/spatial impact of BRG1 and CHD4 on venous and lymphatic identity will be discerned using an array of genetic tools. Venous and lymphatic markers in mutant embryos will be analyzed throughout development to determine precisely when and where BRG1 and CHD4 affect these vessels. Secondly, the epigenetic impact of BRG1 and CHD4 on Coup-TFII expression in veins and lymphatics will be examined. COUP-TFII expression in Brg1 and Chd4 mutants will be correlated with the ve- nous and lymphatic specification phenotypes defined in Aim 1. In addition, primary and cultured endothelial cells will be used to test the hypothesis that BRG1 and CHD4 directly promote vascular Coup-TFII expression through nucleosome remodeling and histone acetylation at the Coup-TFII promoter. The proposed research is significant because it will provide novel information about how chromatin-remodeling enzymes affect Coup-TFII expression and will serve as a first step toward developing pharmacological strategies to manipulate Coup-TFII expression in order to positively or negatively influence vascular development. This research is innovative be- cause it emphasizes epigenetic regulation of vascular development, which deviates from traditional ways of approaching this subject.

描述（由申请人提供）：表观遗传调节剂在各种发育过程中起着重要作用，但是关于它们如何调节血管规范的了解很少。申请人实验室的一个长期目标是了解ATP依赖性染色质复合物如何表观遗传调节基因的转录，这些基因与发育和产后血管病理相关的基因，例如由血液和淋巴管的未指定产生的基因。该提案的目的是了解染色质复制酶BRG1和CHD4如何影响胚胎发育过程中的静脉和淋巴认同。 Central假设是，BRG1和CHD4通过调节核受体COUP-TFII的血管表达来影响静脉和淋巴认同。该假设基于申请人实验室中产生的初步数据以及血管BRG1，CHD4和COUP-TFII突变小鼠Embryos之间的表型相似性。 COUP-TFII在静脉和淋巴规格中起着重要作用，但对于促进其血管表达的原因却一无所知。因此，鉴定表观遗传机制来调节其升高，将阐明政变-TFII如何影响血管发展。将采用两个具体目标来检验中心假设。首先，将使用一系列遗传工具来识别BRG1和CHD4对静脉和淋巴认同的时间/空间影响。将在整个发育过程中分析突变胚胎中的静脉和淋巴标记，以确定BRG1和CHD4影响这些血管的何时何地。其次，将检查BRG1和CHD4对静脉和淋巴管中政变-TFII表达的表观遗传影响。 BRG1和CHD4突变体中的COUP-TFII表达将与AIM 1中定义的Ves nous和lymphatic Specification表型相关。此外，原代和培养的内皮细胞将用于测试BRG1和CHD4直接通过核组促进型甲基化和组成型甲基化的丙烯酸酯促进的假说，即直接促进血管-TFII的表达。拟议的研究之所以重要，是因为它将提供有关染色质复制酶如何影响政变TFII表达的新信息，并将成为开发药理学策略以操纵政变TFII表达以积极或负面影响血管发育的第一步。这项研究具有创新性，因为它强调了对血管发展的表观遗传调节，这偏离了接近该主题的传统方式。