Transcriptional Control of Endothelial Differentiation

内皮分化的转录控制

• 批准号: 8468731
• 负责人: NATHAN D LAWSON
• 金额: $ 38.76万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468731
• 关键词: Adult; Affect; Alleles; Animals; Appearance; Arteries; Automobile Driving; Beryllium; Biological Models; Blood Cells; Blood Vessels; Cell Differentiation process; Cell Line; Cells; Development; Disease; Down-Regulation; Embryo; Embryonic Development; Endoderm; Endothelial Cells; Gene Expression; Gene Targeting; Genes; Genetic Epistasis; Knock-out; Location; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Profiling; Morphogenesis; Mus; Neural Crest; Organism; Pathologic Neovascularization; Pattern; Play; Process; Proteins; Regulation; Regulator Genes; Reporter; Ring Finger Domain; Role; Signal Transduction; Staging; Stem cells; Tissue Engineering; Tissues; To specify; Transcriptional Regulation; Transgenic Organisms; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Vascular Diseases; Vascular Endothelial Growth Factors; Venous; Work; Zebrafish; base; cell type; chromatin immunoprecipitation; genome-wide; human disease; in vivo; knock-down; malformation; programs; public health relevance; research study; tissue regeneration; transcription factor; tumor growth

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.

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至关重要。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分化的分子基础是非常相关的。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，但人们对内皮细胞中的此类程序知之甚少。由于控制病理性新生血管形成的信号在正常血管发育过程中也在胚胎中使用，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这一过程。在本提案中，我们将利用斑马鱼作为模型系统的诸多优势来定义 Ets 转录因子 etv2 在内皮细胞特化过程中的作用。我们将研究在翻译后和转录水平上负责 Etv2 调节的机制。我们还将确定与内皮规范相关的 etv2 的直接靶标，特别强调编码转录因子的基因。随后我们将鉴定由 etv2 和下游转录因子启动的调控基因程序，并确定它们如何促进内皮分化。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。