Regulation of angiogenesis by transcription factors

 描述（由申请人提供）：血管生成，即新血管的形成，是生长和修复所必需的，并且血管生成的不规则性导致许多恶性、炎症和缺血性疾病。调节血管生成基因表达的转录因子对血管的正常发育和体内平衡至关重要。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血管完整性的维持中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Yin Yang 1（YY 1）是一种普遍表达的含GLI-Krüppel锌指的转录因子，有助于各种正常的生物学过程，包括发育，分化和细胞增殖。然而，YY 1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，内皮细胞特异性敲除小鼠YY 1基因导致与血管发育和血管生成缺陷相关的妊娠中期胚胎死亡。YY 1缺陷的内皮细胞和卵黄囊的基因谱分析识别了许多改变的基因，特别感兴趣的是Notch信号依赖性基因。越来越多的证据支持Notch信号通路的微调控制血管系统的正常发育。因此，我们推测YY 1通过调节Notch依赖的基因转录来调节内皮细胞的特异性、功能和血管生成。将采用分子、细胞和小鼠模型的组合来确定YY 1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YY 1调节Notch依赖性血管生成相关基因的分子机制; 2）确定内皮YY 1在调节内皮细胞特化和出芽血管生成中的生物学作用和分子机制; 3）描述内皮YY 1在调节成人缺血性血管生成中的生理作用和分子机制。从这些研究中收集到的信息对于确定YY 1等转录因子的操作对于设计血管生成相关疾病的新型有效疗法至关重要。

 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.