Our long-term goal is to ascertain the molecular mechanisms responsible for the normal development and maintenance of the mammalian vasculature and to elucidate molecular lesions underlying vascular pathogenesis. Recent experiments performed on zebrafish have suggested that Notch expression provokes arterial development while its down-regulation results in the default development of veins. Despite these findings in zebrafish, mouse knockout experiments suggest Notch's role in mammilian arterial-venous (AV) development is more complex. Furthermore, the precise cellular and molecular events remain to be defined. To determine the function of the Notch pathway in AV differentiation both in mouse embryos and adults, our lab has developed a mouse model, in which a constituitively active form of Notch is expressed exclusively in endothelial cells. Furthermore, the activated Notch expression is temporally regulatable, thereby allowing us to examine its effects in both developmental and adult vasculature. Using this and other Notch mutants, we will accomplish the following specific aims: define the role of Notch in embryonic AV differentiation (Aim 1); define the role of Notch in adult maintenance of AV identity (Aim 2); define the cellular mechanisms by which Notch specifies differentiation of arteries and veins (Aim 3); and identify the molecular events triggered by Notch in endothelial cells (Aim 4).
The specific aims of this study, engaging morphological, cellular, and molecular analyses, entail both gain-and loss-of-function studies of Notch in endothelial cells. These efforts will reveal the role of Notch in vascular differentiation and maintenance and illuminate potential molecular mechanisms underlying these processes. In the future, this basic understanding of Notch in pre and postnatal mammalian vascular function will guide investigations into its function under pathological conditions, such as ischemic collateral artery formation. Ultimately, our understanding of the Notch pathway may lead to the identification of novel drug targets and therapeutic interventions to vascular diseases.
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