Transcriptional Control of Endothelial Differentiation

内皮分化的转录控制

• 批准号: 7987723
• 负责人: NATHAN D LAWSON
• 金额: $ 41.13万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987723
• 关键词: Adult; Affect; Alleles; Animals; Appearance; Arteries; Automobile Driving; Biological Models; Blood Cells; Blood Vessels; Cell Differentiation process; Cell Line; Cells; Development; Disease; Down-Regulation; Elements; Embryo; Endoderm; Endothelial Cells; Gene Expression; Gene Targeting; Genes; Genetic Epistasis; Human; Knock-out; Location; Malignant Neoplasms; 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. 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.

描述（由申请人提供）：内皮细胞分化对正常和疾病情况下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正常的血管模式和循环功能至关重要。在一些先天性血管疾病的病例中，内皮分化受到干扰导致血管畸形。在其他情况下，通过调节内皮细胞分化，积极规划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非常重要的。虽然负责细胞分化的转录等级在其他组织中已被广泛表征，但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也在胚胎正常血管发育过程中使用，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许多优点来定义Ets转录因子etv2在内皮规范中的作用。我们将在翻译后和转录水平上研究负责Etv2调控的机制。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。我们随后将确定由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。