Identifying Vegf target genes during artery development

鉴定动脉发育过程中的 Vegf 靶基因

• 批准号: 6808285
• 负责人: NATHAN D LAWSON
• 金额: $ 8.1万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808285
• 关键词: angiogenesis; biological signal transduction; cell differentiation; embryo /fetus; genetic manipulation; genetically modified animals; in situ hybridization; microarray technology; pathologic process; vascular endothelial growth factors; vascular endothelium; zebrafish

DESCRIPTION (provided by applicant): Molecular distinction between the endothelial cells that line arteries and veins is required for normal blood vessel formation during embryonic development. Evidence indicates that these differences are determined by the complex genetic interaction of the Sonic hedgehog, Vascular endothelial growth factor (Vegf), and Notch signaling pathways. Abnormal blood vessel formation is associated with a wide range of early childhood disorders and human diseases, including cancer and diabetes. Therefore, a better understanding of the signals that govern artery and vein identity will aid in the therapeutic manipulation of blood vessel formation during disease progression. In this application, the principal investigator will use a variety of benefits afforded by the use of the zebrafish as a model system to identify targets of Vegf during embryonic blood vessel development. This will be accomplished by combining microarray analysis with the ability to manipulate the Vegf pathway in vivo in zebrafish embryos. Following microarray analysis, the investigator will determine the response of Vegf target genes to components of the arterial differentiation pathway using whole mount in situ hybridization in zebrafish embryos following a number of different genetic manipulations. The investigator's demonstrated ability to specifically modulate arterial endothelial cell development in zebrafish transgenic and mutant lines will allow the determination of which putative Vegf target gene(s) may be important for arterial endothelial cell differentiation. Together, these studies will permit the identification of components of the signaling pathways that govern arterial endothelial cell fate, and will serve as a foundation for future functional characterization of these putative regulators.

描述（由申请人提供）：胚胎发育期间正常血管形成需要动脉和静脉内皮细胞之间的分子区别。 有证据表明，这些差异是由 Sonic hedgehog、血管内皮生长因子 (Vegf) 和 Notch 信号通路的复杂遗传相互作用决定的。 血管形成异常与多种早期儿童疾病和人类疾病有关，包括癌症和糖尿病。 因此，更好地了解控制动脉和静脉特性的信号将有助于在疾病进展过程中对血管形成进行治疗性操作。 在此应用中，主要研究人员将利用斑马鱼作为模型系统所带来的各种好处来识别胚胎血管发育过程中 Vegf 的靶标。 这将通过将微阵列分析与在斑马鱼胚胎体内操纵 Vegf 通路的能力相结合来实现。 微阵列分析后，研究人员将在斑马鱼胚胎中进行整体原位杂交，并进行多种不同的基因操作，以确定 Vegf 靶基因对动脉分化途径成分的反应。 研究人员已证明能够特异性调节斑马鱼转基因和突变系中动脉内皮细胞的发育，这将有助于确定哪些推定的 Vegf 靶基因可能对动脉内皮细胞分化很重要。 总之，这些研究将允许识别控制动脉内皮细胞命运的信号通路的组成部分，并将为这些假定的调节因子的未来功能表征奠定基础。