Transcriptional Control of Endothelial Differentiation

描述（由申请人提供）：内皮细胞分化对于正常和疾病环境中的血管发育和功能至关重要。例如，在发育中的胚胎中，动脉和静脉内皮细胞的分化对于适当的血管模式和循环功能是必不可少的。在某些先天性血管疾病的情况下，内皮分化受到干扰，导致血管畸形。在其他情况下，通过调节内皮分化来主动编程血管识别将是有益的。因此，更好地了解正常内皮细胞分化的分子基础是高度相关的。虽然负责细胞分化的转录层次结构已在其他组织中得到广泛表征，但对内皮细胞中的此类程序知之甚少。由于支配病理性新血管形成的信号在正常血管发育期间也用于胚胎中，并且这些信号在进化上是保守的，因此可以使用模型系统来研究该过程。在这个提议中，我们将利用斑马鱼作为模型系统的许多好处来定义Ets转录因子etv2在内皮细胞特化过程中的作用。我们将调查负责Etv2在翻译后和转录水平的调节机制。我们还将确定直接目标etv2相关的内皮规格，特别强调基因编码的转录因子。随后，我们将确定由etv2和下游转录因子启动的调控基因程序，并确定这些基因程序如何促进内皮细胞分化。最后，我们将确定其他Ets转录因子在转导外部信号以驱动动脉基因表达和形态发生中的作用。 公共卫生相关性：血管根据其解剖位置具有不同的功能和外观。这些差异在早期胚胎以及疾病环境中都很明显，例如癌症期间与肿瘤生长相关的血管形成。然而，人们对这些差异是如何产生的知之甚少。在这项提议中，我们将利用斑马鱼作为一个模型系统，以确定在发育中的胚胎中控制血管身份的基因程序。

DESCRIPTION (provided by applicant): Endothelial cell differentiation is essential for blood vessel development and function in both normal and disease settings. For example, in the developing embryo differentiation of arterial and venous endothelial cells is essential for proper vessel patterning and circulatory function. In some cases of congenital vascular disease, endothelial differentiation is perturbed leading to vascular malformations. In other cases, it would be beneficial to actively program blood vessel identify by modulating endothelial differentiation. Thus, a better understanding of the molecular basis of normal endothelial differentiation is highly relevant. While transcriptional hierarchies responsible for cellular differentiation have been extensively characterized in other tissues, much less is known about such programs in endothelial cells. Since the signals that govern pathological neovascularization are also used in the embryo during normal blood vessel development and these signals are evolutionarily conserved, it is possible to study this process using model systems. In this proposal, we will take advantage of the many benefits of the zebra fish as a model system to define the role of the Ets transcription factor, etv2 during endothelial specification. We will investigate the mechanisms responsible for Etv2 regulation at both the post-translational and transcriptional levels. We will also identify direct targets of etv2 relevant to endothelial specification, with a particular emphasis on genes encoding transcription factors. We will subsequently identify regulatory gene programs initiated by etv2 and downstream transcription factors and determine how these contribute to endothelial differentiation. Finally, we will determine the role of other Ets transcription factors in transducing external signals to drive artery gene expression and morphogenesis. PUBLIC HEALTH RELEVANCE: Blood vessels have different functions and appearances depending on their anatomical location. These differences are apparent in early embryos, as well as in disease settings, such as blood vessel formation associated with tumor growth during cancer. However, little is known about how these differences arise. In this proposal, we will utilize the zebra fish as a model system to identify gene programs that govern blood vessel identity in the developing embryo.