Investigating the role of endothelial expression of Slug in angiogenesis

研究 Slug 内皮表达在血管生成中的作用

• 批准号: 9051441
• 负责人: Nan Wu Hultgren
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9051441
• 关键词: Affect; Angiogenic Factor; Animal Model; Area; BMP4; Behavior; Biological Assay; Biology; Blood Vessels; Cancer Biology; Cells; Characteristics; Clinical; Data; Data Analyses; Defect; Development; Drug Targeting; Embryonic Development; Endothelial Cells; Equilibrium; Experimental Designs; FDA approved; Family; Feedback; Fibrin; Fibrosis; Future; Gatekeeping; Gel; Gene Expression; Gene Proteins; Genetic Transcription; Growth; Growth and Development function; Image; In Vitro; Instruction; Investigation; Knockout Mice; Lead; Life; Light; Malignant Neoplasms; Mediating; Mesenchymal; MicroRNAs; Mission; Modeling; Molecular Profiling; Molecular and Cellular Biology; Mus; Names; National Heart, Lung, and Blood Institute; Neonatal; Neoplasm Metastasis; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Pattern; Pericytes; Phenotype; Primary Neoplasm; Process; Psyche structure; Public Health; Regulation; Regulatory Pathway; Reporter; Reporting; Research Personnel; Retina; Retinal; Role; Signal Transduction; Snails; Solid; Solid Neoplasm; Survival Rate; TNF gene; Techniques; Testing; Time; Tissues; Training; Transforming Growth Factor beta; Tumor Angiogenesis; Vascular Diseases; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; blood vessel development; cancer therapy; career development; cell motility; cell type; clinical effect; colon cancer cell line; combat; drug development; epithelial to mesenchymal transition; improved; in vivo; in vivo Model; knock-down; knockout animal; matrigel; member; neoplastic cell; new therapeutic target; notch protein; novel; overexpression; prevent; promoter; public health relevance; slug; targeted treatment; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression

 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.

 描述(申请人提供)：这项拟议的研究旨在阐明Slug转录因子在调控萌芽血管生成中的作用，以及所采用的潜在机制。Slug(SNAI2)是高度保守的Snail转录因子家族中的一员，可以诱导上皮间充质转化(EMT)，这是胚胎发育和组织纤维化和癌症转移等病理条件下的一个重要过程。在内皮细胞(EC)中也发生了类似的过程，称为内皮细胞向间充质细胞的转变(EndoMT)，这也可以受到Slug的调节。我们最近的研究表明，Slug在EC中的表达对于体外血管生成至关重要，可能是通过诱导部分EndoMT来实现的。有趣的是，之前还没有在鼻涕虫缺陷小鼠中发现血管缺陷的报道。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血管生成方面的缺陷。我们还报道，在血管生成的内皮细胞中，Slug的过度表达促进EndoMT样行为的增强。然而，Slug介导的EndoMT在萌芽血管生成过程中所涉及的确切靶点和机制尚不清楚。这项拟议的工作将首先测试在粘蛋白缺陷小鼠中看到的血管缺陷是否是由于EC本身中粘蛋白的丢失(迄今为止的所有证据都表明是这种情况)，然后将检查粘蛋白在EC中的表达水平如何决定细胞是经历部分EndoMT来形成新血管，还是经历类似于未成熟和混乱的肿瘤血管的完整EndoMT。最后，我们将测试内源性MT启动因子，如肝细胞生长因子和肿瘤坏死因子α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。鉴于已有的研究和我们的初步数据，我们假设由前EndoMT因子诱导的Slug表达水平控制着体内萌发的血管生成。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，揭示肿瘤血管生成的独特和新的特征，并为促进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抗击癌症来促进健康生活。