A Nuclear Receptor COUP-TFII in Cardiovascular Function

核受体 COUP-TFII 对心血管功能的影响

• 批准号: 6874051
• 负责人: SOPHIA Y. TSAI
• 金额: $ 37.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874051
• 关键词: angiogenesis; cardiogenesis; cardiovascular function; congenital heart septum defect; developmental genetics; endocardium; gene mutation; genetically modified animals; laboratory mouse; microarray technology; myocardium; nuclear receptors; receptor expression; transcription factor; vascular endothelium

DESCRIPTION (provided by applicant): COUP-TFII is an orphan nuclear receptor that belongs to the steroid receptor superfamily. Ablation of COUP-TFII in mice results in early embryonic lethality due to defects in angiogenesis and heart development. To further understand the biological functions of COUP-TFII in vascular and heart development, LacZ knock-in and floxed COUP-TFII mice were generated. X-Gal staining of the LacZ knock-in mice shows high COUP-TFII expression in the endothelium of the vein but not in the artery. Further, chimera analysis showed that COUP-TFII plays a cell autonomous function in the endothelial cells of the vein but not the artery. These studies show for the first time that COUP-TFII is an essential transcription factor for vein identify. The insertion of loxP site into the COUP-TFII locus reduced the expression of COUP-TFII, rendering the COUP-TFII flox/- mutants genetically hypomorphic. The hypomorphic mutants exhibit atrioventricular septal defects (AVSD) commonly observed in congenital heart disease patients. The atrium malformation displayed by the COUP-TFII null mutant coupled with AVSD elicited by the hypomorphic mutant together suggest that COUP-TFII plays a critical role in cardiogenesis. Whether the heart defects are intrinsic or secondary to the vascular defects is currently unknown. Proper heart development requires the coordinated interactions between the endocardium and myocardium. Whether the endothelial cells in the endocardium or the myocardial cells in the myocardium are the targets of COUP-TFII regulation is also unclear. To elucidate the role of COUP-TFII in the maintenance of vein identity and in heart development, two Specific Aims are proposed. In Aim 1, we will employ gain-of-function and loss-of-function of COUP-TFII in the endothelial cells to examine the role of COUP-TFII in the maintenance of arteriovenous identity. In addition, we will use DMA chip microarray analysis to identify novel downstream targets and signaling pathways that are regulated by COUP-TFII in the arteriovenous decision. In Aim 2, we will use the hypomorphic mutant and the endothelial and myocardial conditional COUP-TFII knockouts to investigate the role of COUP-TFII in heart development. This study will enable us to determine how endothelial COUP-TFII versus myocardial COUP-TFII affects cardiogenesis and how COUP-TFII modulates the interaction between the myocardium and endocardium. Our proposed studies should provide timely new insights into how COUP-TFII impacts cardiovascular development and facilitate the diagnosis and treatment of congenital heart disease.

描述（由申请人提供）：COUP-TFII是属于类固醇受体超家族的孤儿核受体。由于血管生成和心脏发育缺陷，小鼠政变TFII的消融导致早期胚胎致死性。为了进一步了解政变在血管和心脏发育中的生物学功能，产生了LACZ敲击和Floxed Coup-TFII小鼠。 LACZ敲入小鼠的X-GAL染色在静脉内皮中显示出高的政变-TFII表达，但在动脉中不显示。此外，Chimera分析表明，Coup-TFII在静脉的内皮细胞中扮演细胞自主功能，而不是动脉。这些研究首次表明政变 - TFII是静脉识别的基本转录因子。 LOXP站点插入COUP-TFII基因座降低了COUP-TFII的表达，从而使COUP-TFII FLOX/ - 突变体在遗传上造成型型肌差。型型突变体表现出在先天性心脏病患者中通常观察到的心室间隔缺陷（AVSD）。由政变无效突变体展示的中庭畸形，以及肌阵容突变体引起的AVSD，这表明COUP-TFII在心脏病发生中起着至关重要的作用。目前尚不清楚心脏缺陷是固有的还是继发于血管缺陷的。适当的心脏发育需要心内膜和心肌之间的协调相互作用。无论是内膜内皮细胞还是心肌中的心肌细胞是政变调节的靶标，也不清楚。为了阐明政变在维持静脉身份和心脏发展中的作用，提出了两个具体目标。在AIM 1中，我们将利用功能障碍和在内皮细胞中的功能丧失，以检查政变-TFII在维持动静脉身份中的作用。此外，我们将使用DMA芯片微阵列分析来确定在动脉底决策中受政变TFII调节的新型下游目标和信号通路。在AIM 2中，我们将使用型型突变体以及内皮和心肌有条件的政变TFII敲除来研究政变 - TFII在心脏发展中的作用。这项研究将使我们能够确定内皮coup-TFII与心肌coup-TFII如何影响心脏发生，以及政变-TFII如何调节心肌和心内膜的相互作用。我们提出的研究应及时提供有关政变如何影响心血管发展并促进先天性心脏病的诊断和治疗的新见解。