Regulation of angiogenesis by transcription factors

 描述(申请人提供)：血管生成，即新血管的形成，对生长和修复是必不可少的，血管生成的不规律导致了许多恶性、炎症性和缺血性疾病。调节血管生成基因表达的转录因子对血管的正常发育和动态平衡至关重要。越来越多的证据表明，内皮细胞转录的组合调控在血管网络的形成和维持血管完整性方面起着至关重要的作用。我们的主要目标是阐明与血管生成相关的转录调控，特别是负责正确的内皮细胞分化、发芽和血管重塑的转录因子的相互作用。转录因子阴阳1(YY1)是一种普遍表达的含Gli-Krüppel锌指的转录因子，参与发育、分化和细胞增殖等多种正常生物学过程。然而，YY1在心血管系统中的生物学作用仍然知之甚少。我们的初步研究表明，在小鼠中，内皮细胞特异性的YY1基因敲除会导致与血管发育和血管生成缺陷相关的中期胚胎死亡。YY1缺陷的内皮细胞和卵黄囊的基因图谱分析发现了一些变化的基因，特别感兴趣的是Notch信号依赖基因。越来越多的证据支持，Notch信号通路的微调控制着血管系统的正常发育。因此，我们假设YY1通过调节Notch依赖的基因转录来调节内皮细胞的规格、功能和血管生成。我们将结合分子、细胞和小鼠模型来确定YY1对基因表达、内皮功能和血管生成的影响。因此，我们建议：1)确定YY1调控Notch依赖的血管生成相关基因的分子机制；2)确定内皮细胞YY1在调控内皮细胞规格和萌发血管生成中的生物学作用和分子机制；3)阐明内皮细胞YY1在成人缺血性血管生成调控中的生理作用和分子机制。从这些研究中收集的信息对于确定YY1等转录因子的操作对于设计新的和有效的血管生成相关疾病治疗方法至关重要。

 DESCRIPTION (provided by applicant): Angiogenesis, the formation of new blood vessels, is essential for growth and repair, and an irregularity of angiogenesis contributes to numerous malignant, inflammatory and ischemic disorders. Transcription factors that regulate angiogenic gene expression are critical for proper vascular development and homeostasis. Increasing evidence suggests that the combinatorial regulation of endothelial cell transcription plays a crucial role in vascular network formation and maintenance of vascular integrity. Our major goal is to elucidate the transcriptional governance associated with angiogenesis, specifically the interplay of the transcription factors responsible for correct endothelial cell differentiation, sprouting and vascular remodeling. The transcription factor Yin Yang 1 (YY1) is a ubiquitously expressed GLI-Krüppel zinc finger-containing transcription factor and contributes to various normal biological processes, including development, differentiation, and cellular proliferation. However, the biological role of YY1 in cardiovascular system remains poorly understood. Our preliminary studies show that endothelial cell-specific knockout of YY1 in mice leads to the mid-gestational embryonic lethality associated with defects of vascular development and angiogenesis. Gene profile analysis of YY1 deficient endothelial cells and yolk sac recognized a number of altered genes, of particular interest was Notch signaling-dependent genes. Increasing evidence supports that the fine-tuning of the Notch signaling pathway governs the proper development of the vascular system. Thus, we hypothesize that YY1 regulates endothelial cell specification, function and angiogenesis through modulating Notch-dependent gene transcription. A combination of molecular, cellular and mouse models will be employed to establish the influence of YY1 on gene expression, endothelial function and angiogenesis. As such, we propose: 1) to determine the molecular mechanisms by which YY1 regulates Notch-dependent angiogenesis-associated genes; 2) to define the biological role and molecular mechanisms of endothelial YY1 in regulation of endothelial cell specification and sprouting angiogenesis; 3) to delineate the physiological role and molecular mechanisms of endothelial YY1 in regulation of ischemic angiogenesis in adults. The information gleaned from these studies is critical to determine how manipulations of transcription factors such as YY1 are critica for designing novel and effective therapies for angiogenesis-related diseases.