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. ? ? ?
| Covassin, Laurence; Amigo, Julio D; Suzuki, Kana et al. (2006) Global analysis of hematopoietic and vascular endothelial gene expression by tissue specific microarray profiling in zebrafish. Dev Biol 299:551-62 |
