Molecular mechanisms of fibrin functions at the neurovascular interface

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The role of the brain vasculature has been recently extended from a supplier of nutrients to an angiogenic niche that drives axon guidance during development and adult neurogenesis. The identification of novel factors responsible for neurovascular communication is necessary for the molecular understanding of neuronal survival and neurogenesis. Studies at the host lab have identified fibrin, a blood-derived protein deposited in the nervous system after perturbations of the neurovascular homeostasis, as an inhibitor of neuronal regeneration and a regulator of demyelination in the CNS. Fibrin interacts with a plethora of receptors and mediates signaling pathways that control cell survival, differentiation and activation. Although the signaling machinery necessary for fibrin actions is present in both neuronal cells and mediators of neuronal functions, such as microglia cells, the effects of fibrin in the nervous system have not been characterized. The central goal of this project is to understandthe molecular basis of fibrin signaling on neuronal survival and neurogenesis. The studies in this project will involve the identification and characterization of the cellular players, the receptors and signaling mechanisms used by fibrin to mediate its effects in the nervous system using state-of-the-art in vivo and in vitro techniques.