Research: Vascular Development
One of the major research focuses in the laboratory is to understand the molecular mechanisms underlying blood vessel development. Although many growth factors and their receptors have been identified that are critical for blood vessel development, much less is known about the transcription factors that regulate this process and may serve as master switches for initiating these events. As an example, we have focused on the transcriptional regulation of the Tie1 and Tie2 genes. These are tyrosine kinases that are required for vascular development. The genomic regulatory elements required for the vascular-specific expression of these genes have been identified but not the transcription factors that are required to express the Tie genes. We have identified conserved binding sites for members of the Ets transcription factor family within the regulatory regions of these genes. Mutations in these binding sites lead to a marked reduction in the vascular specific expression of these genes.
The Ets factors are a family of highly conserved transcription factors that are involved in regulating development and cellular differentiation. Among the Ets factors, we have identified NERF and ELF-1 as potent transactivators of the Tie genes. We have identified specific binding sites within the regulatory regions of these genes. Using the chicken model of vascular development, we have identified the chicken homologue of the Ets factor ELF-1 as being enriched in developing blood vessels. In addition to their known role in hematopoiesis, our studies demonstrate a dual role for selected members of the Ets factor family such as NERF and ELF-1 in blood vessel development and hematopoiesis.
Another area of interest in the laboratory is endothelial differentiation. Using embryonic stem cells, we have identified selected transcription factors that are differentially expressed during the process of endothelial differentiation. One factor of particular interest to our laboratory is the Ets factor ERG. ERG is highly enriched in endothelial cells and is expressed early during the process of endothelial differentiation. Studies are currently underway to further define the role of ERG as a transcriptional regulator of endothelial differentiation and vascular development.