TRANSCRIPTIONAL MECHANISMS OF ENDOTHELIAL FUNCTION AND DIFFERENTIATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在胚胎发育期间，早期血管丛通过称为血管发生的过程形成。响应于生长因子，内皮前体细胞分化为内皮细胞并迁移以形成新的血管。然后，早期的血管丛通过血管生成而延伸，其中新血管由现有血管形成。在成人中，血管生成还涉及多种生理和病理（例如肿瘤血管生成）状况。 血管内皮生长因子受体酪氨酸激酶家族（VEGFR receptor tyrosine kinases，RTKs）在胚胎血管发育以及成人生理和病理性血管生成过程中起重要作用，多种转录因子（ETS）和缺氧诱导因子（hypoxia inducible factors，HIFs）参与了内皮细胞特异性基因表达的建立。因此，我们假设血管生成信号-ETS1/HIF-2 α轴调节血管内皮细胞中VEGF受体和其他关键基因的转录。在这项研究中，使用获得和功能丧失的方法与小鼠胚胎干细胞（ES细胞）分化系统，我们将测试是否ETS1和HIF-2 α调节血管内皮细胞分化过程中的VEGFR表达。将对ES细胞、ES细胞衍生的内皮祖细胞和内皮细胞进行分析，以检验内皮分化期间VEGFR1和VEGFR2染色质结构域受ETS1和HIF-2 α调节的假设。此外，我们将通过产生缺乏ETS1和HIF-2 α的小鼠来确定ETS1和HIF-2 α在血管发育过程中功能合作的重要性。 血管生成对于包括肿瘤生长/转移的某些病理学病症是关键的。 从这些研究中收集的信息将有助于我们了解血管生成的分子机制，并有望导致新的治疗方式。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. During embryonic development the early vascular plexus forms through the process called Vasculogenesis, In response to growth factors, endothelial precursor cells differentiate to endothelial cells and migrate to form new blood vessels. The early vascular plexus is then extended through angiogenesis in which new vessels are formed from existing vessels. In adults, angiogenesis is also involved in multiple physiological and pathological (e.g. tumor angiogenesis) conditions. VEGFR family of receptor tyrosine kinases (RTKs) are crucial for vascular development during embryogenesis as well as physiological and pathological angiogenesis in adults.Multiple transcription factors, including ETS and hypoxia inducible factors (HIFs)have been implicated in establishing endothelial cell-specific gene expression. So, we hypothesize that an angiogenic signal-ETS1/HIF-2alpha axis regulates transcription of VEGFRs and other key genes in vascular endothelium. In this study, using gain-in- and loss-of-function approaches with mouse embryonic stem cell (ES cell) differentiation system, we will test whether ETS1 and HIF-2alpha regulate VEGFR expression during endothelial differentiation. Analysis will be performed with ES cells, ES cell-derived endothelial progenitor cells and endothelial cells to test the hypothesis that during endothelial differentiation VEGFR1 and VEGFR2 chromatin domains are regulated by ETS1 and HIF-2alpha. In addition, we will determine the importance of the functional co-operation of ETS1 and HIF-2alpha during vascular development by generating mice lacking both ETS1 and HIF-2alpha. Angiogenesis is critical for certain pathological disorders including tumor growth/metastasis. Information gleaned from these studies will contribute to our understanding of the molecular mechanisms of angiogenesis and hopefully will lead to novel therapeutic modalities.