Centrosome Mis-Regulation and Blood Vessel Function

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DESCRIPTION (provided by applicant): Centrosomes nucleate microtubules in cells, and organize them via a microtubule organizing center (MTOC) during interphase and via spindles during mitosis. Centrosome duplication is normally tightly regulated to occur once and only once per cell cycle, and loss of this regulation leads to excess centrosomes, genetic instability, and aneuploidy in tumor cells. We recently showed, for the first time, that endothelial cells (EC) in blood vessels exposed to elevated VEGF-A signaling have excess centrosomes, mediated through Akt, MEK/ERK, and Cdk2/cyclin E. Centrosome excess is predicted to perturb the cytoskeleton and result in alterations in cellular behaviors, although this link has not been made in cells or tissues; it also is predicted to produce chromosome instability and aneuploidy, leading to EC with profound changes from the norm. This work will test the hypothesis that excess centrosomes in EC perturb vessel function via both mitotic and non-mitotic perturbations, and examine the mechanisms that lead to centrosome mis-regulation upon angiogenic factor stimulation. This highly innovative hypothesis will be tested with three aims that address the questions: 1) What are the inputs and mechanisms that lead to EC centrosome mis- regulation? 2) What are the consequences of excess centrosomes to EC behaviors and sprouting? and 3) what are the outcomes of excess centrosomes in EC of vessels in vivo? We will utilize cell- based models of blood vessel formation and in vivo mouse developmental and disease models to address the questions. The significance of this work will be to reveal susceptibility in developing vessels for centrosome-mediated EC dysfunction and genetic instability, which is predicted to contribute to blood vessel dysfunction in novel ways, and lead to new and distinct therapeutic targets.