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Harnessing LOX towards dissecting the mechanisms underlying aortic aneurysm formation

Vascular smooth muscle cells (VSMCs) play key roles in development, function and homeostasis of the vasculature. Disruption to VSMC function results in vascular pathologies including aortic aneurysms (AA) which account for more than 30,000 deaths per year in the USA. Approximately 75% of all patients with ruptured AA die from the condition demonstrating the urgent need to identify associated genes and underlying processes. We propose to identify the sequence of events leading to AA formation and the key genes involved. Disruption to the activity of the extracellular-matrix (ECM) modifying enzyme Lysyl-oxidase (LOX) have been associated with AA in humans and mice. We now take advantage of the Lox conditional knockout mice we have generated which allow us to delete it in a Cre-dependent manner. We find its deletion specifically in the VSMCs leads to disruption of vascular integrity and lethality. Importantly, our preliminary results suggest that apart from its classical ECM activities, LOX plays multiple roles in VSMCs including regulation of cytoskeleton formation advocating the option that AA caused following LOX mutation or pharmacological inhibition are not strictly due to defective ECM but rather are also due to abnormal cell behavior. By combining the multiple tools we have generated, which include primary cell culture, in-vivo genetic manipulations and RNAseq analyses of VSMC translatome we aim to follow the transcriptional changes that occur prior to, during and following AA development in order to generate a sequence of events involved in its formation, so future screening processes could identify people at risk

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