B-RAF Drives Regenerative Axon Growth in the Optic Nerve in vivo

Our goal is to enable CNS axon regeneration by elevating intrinsic growth signaling. The RAF kinase is known to drive fast axon growth in embryonic sensory neurons; we therefore will now activate this kinase in the retina. Our first aim is to promote regeneration in the injured optic nerve using a conditional B-RAF gain-of-function mouse model. We will then test the roles of signaling molecules downstream of RAF signaling - the MEKs, ERKs and RNDs - for their contributions to B-RAF-driven retinal axon regeneration (Aim 2). Next, we plan to combine activation of B-RAF with activation of PI3-kinase signaling (using a knock-out of the PI3-kinase antagonist PTEN) to see whether this combination will further boost regenerative optic nerve axon growth in vivo (Aim 3). If we can observe regeneration into any of the optic tract nuclei, we will test the mice for any recovery of visual function; such functional recovery being the ultimate goal of all axon regeneration studies. The proposed study will define the roles of RAF signaling and its downstream effectors in the context of optic nerve regeneration, laying groundwork for translational research and for the identification of novel drug targets.