Investigating the role of endothelial expression of Slug in angiogenesis

 描述（由申请人提供）：拟议的研究旨在阐明Slug转录因子在调节出芽血管生成中的作用，以及所采用的潜在机制。Slug（Snai 2）是高度保守的Snail转录因子家族的成员，并且已知其诱导上皮-间充质转化（EMT），这是胚胎发育和病理条件（如组织纤维化和癌症转移）的重要过程。类似的过程发生在内皮细胞（EC）中，称为内皮-间充质转化（EndoMT），这也可以由Slug调节。我们最近的研究表明，在EC中的Slug表达是至关重要的萌芽血管生成在体外，可能通过诱导部分EndoMT。有趣的是，血管缺陷以前没有记录在蛞蝓缺陷小鼠。然而，在使用这些小鼠的初步研究中，我们观察到发育和病理性血管生成的缺陷。我们还报道了Slug的过表达促进血管生成EC中增强的EndoMT样行为。然而，Slug介导的EndoMT在出芽血管生成过程中的确切靶点和机制尚不清楚。提出的工作将首先测试在Slug缺陷小鼠中观察到的血管缺陷是否是由于EC本身中Slug的丢失（迄今为止的所有证据都表明是这种情况），然后将研究EC中Slug表达水平如何决定细胞是否经历部分EndoMT以形成新血管，或者类似于未成熟和混乱的肿瘤血管系统的完整EndoMT。最后，我们将测试EndoMT启动因子如HGF和TNFα是否通过诱导Slug基因表达和蛋白质稳定性来促进血管生成。鉴于现有的研究和我们的初步数据，我们假设由pro-EndoMT因子诱导的Slug表达水平控制体内出芽血管生成。这些目标的完成将显著提高我们对新血管形成的基本机制的理解，阐明肿瘤血管生成的独特和新颖特征，并为促或抗血管生成治疗提供新的药物靶点。拟议研究的范围和潜在的公共卫生影响非常符合NHLBI和NCI的使命，即通过预防血管疾病和对抗癌症来促进健康生活。

 DESCRIPTION (provided by applicant): The proposed study aims to elucidate the role of the Slug transcription factor in regulating sprouting angiogenesis, and the underlying mechanism employed. Slug (Snai2) is a member of the highly-conserved Snail family of transcription factors and is known to induce epithelial-to-mesenchymal transition (EMT), an important process for both embryonic development and pathological conditions such as tissue fibrosis and cancer metastasis. A similar process occurs in endothelial cells (EC), named endothelial-to-mesenchymal transition (EndoMT), and this can also be regulated by Slug. Our recent study demonstrated that Slug expression in EC is vital for sprouting angiogenesis in vitro, potentially by inducing a partial EndoMT. Interestingly, vascular defects have not previously been documented in Slug-deficient mice. However, in a preliminary study using these mice we have observed defects in both developmental and pathological angiogenesis. We have also reported that over-expression of Slug promotes enhanced EndoMT-like behaviors in angiogenic ECs. However, the exact targets and mechanisms involved in Slug-mediated EndoMT during sprouting angiogenesis are unclear. The work proposed will firstly test whether the vascular defects seen in Slug-deficient mice are due to loss of Slug in the EC themselves (all evidence to date points to this being the case), and will then examine how the level of Slug expression in EC determines whether cells undergo a partial EndoMT to form new vessels, or a complete EndoMT which resembles immature and disorganized tumor vasculature. Finally, we will test whether EndoMT-initiating factors such as HGF and TNFα promote angiogenesis by inducing Slug gene expression and protein stability. Given the existing studies and our preliminary data, we hypothesize that the level of Slug expression induced by pro-EndoMT factors controls sprouting angiogenesis in vivo. Completion of these aims will significantly enhance our understanding of the basic mechanisms underlying new blood vessel formation, shed light on unique and novel characteristics of tumor angiogenesis, and present new drug targets for pro- or anti- angiogenic therapies. The scope and potential public health impact of the proposed study fits well with the missions of NHLBI and NCI to promote healthy living by preventing vascular diseases and combating cancer.