Our current research shows that neurotrophin and integrin signaling pathways are required for developmental and regenerative dorsal root ganglion (DRG) axon growth. One previously identified mediator of both NGF and integrin signaling pathways, is integrin-linked kinase (ILK). ILK is a serine/threonine kinase, which is activated via integrin engagement that links NGF signaling to integrin mediated signaling. Inhibition of ILK activity has a strikingly inhibitory effect on developmental axon growth of DRG neurons in vitro. Equally important, I have recently shown that precondition lesion-induced DRG axon outgrowth in adulthood is also completely blocked by an ILK inhibitor in vitro. It is now critical to test the role of ILK on developmental and regenerative axon growth of DRG neurons in vivo. This will be done by breeding ILK fix/fix mice with DRG specific Cre lines including an inducible DRG specific Cre mouse that we have generated and characterized. I will also assess whether ILK's effects on axon growth in vivo are mediated through inactivation of GSK-3beta as we predict based on our in vitro experiments. The proposed experiments will provide a further understanding of mechanisms that regulate axon growth in vivo.
