The overall goal of this proposal is to investigate the molecular mechanisms of vascular development through study of the intracellular signaling pathways that mediate cell-specific expression of developmental genes in endothelial cells. Two endothelial cell-specific receptors, TIE2 and TIE1, play a crucial role in the mid-to-late stages of vascular development. TIE2 mediates events governing sprouting angiogenesis, remodeling of the developing vasculature into small and large vessels, and recruitment of peri-endothelial cells to the vessel wall. TIE1 is required for maintaining the integrity of capillary endothelial cells and for promoting angiogenesis at the level of the capillary network. Characterization of the transcriptional mechanisms that regulate TIE2 and TIE1 has allowed us to identify a DNA octamer element that is required for the in vivo expression of both genes in endothelial cells. Biochemical studies indicate that octamer- mediated gene expression of TIE2 and TIE1 results from its interaction with a protein complex that consists of the ubiquitous transcription factor Oct1 and a novel endothelial cell cofactor we term ECCO. Using a yeast modified one-hybrid screen for Oct1-interacting partners, we have recently isolated a cDNA clone encoding for ECCO. The proposed studies will capitalize on this finding and attempt to pursue biochemical, molecular and genetic studies to determine the role of this novel factor in the development of the vascular system during embryogenesis and in the formation of a neovasculature in adult tissues.
In Specific Aim I, we plan to investigate the molecular nature of the interaction of ECCO with Oct1 and the DNA octamer element.
In Specific Aim II, we propose to pursue studies to determine the timing and pattern of expression of ECCO during embryonic development. This would allow us to place ECCO within the framework of the vascular developmental program in relation to other endothelial and vascular developmental markers. We also propose to investigate, through genetic studies, the in vivo role of ECCO in vascular development through loss-of-function experiments in transgenic mice and in stem cell chimeras.
In Specific Aim III, we plan to examine the expression of ECCO in the vasculature of solid tumors and to begin to determine the possible mechanisms of ECCO-induced angiogenesis Results from the proposed studies are likely to provide important insights into fundamental aspects of endothelial cell biology and vascular development.
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