Corticospinal tract regeneration via NF-kB inhibition
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abstract
The reduced intrinsic growth capacity of adult CNS neurons is a key mechanism underlying failure to regenerate axons following spinal cord injury (SCI). The corticospinal tract (CST), the most functionally important motor pathway in humans, is especially refractory to regeneration after injury. Previous studies have achieved partial regeneration of the lesioned CST via single-gene replacement approaches. However, manipulation of a single gene and its signaling pathway may be insufficient to unlock genetic growth programs that support more extensive regeneration.To identify a set of upstream transcriptional regulators that may activate a broader regeneration program in neurons (i.e., “master regulators” of regeneration), we have combined genome-wide screenings and biological network analysis to identify a set of genes that are expressed in regeneration-enabled neuronal populations. We identified NF-kB as a major “transcriptional hub” in growth-enabled neuronal populations. Overexpression of a potent inhibitor of NF-kB activation, IkBm, in DRG neurons resulted in enhanced regeneration of injured dorsal column axons following SCI, demonstrating a novel role of neuronal NF-kB signaling in axonal regeneration. Because we have also identified NF-kB as a central transcriptional hub in sprouting, uninjured CST neurons, we hypothesize that NF-kB inhibition in injured corticospinal motor neurons will promote axonal regeneration and enhance recovery of CST-dependent function following SCI.To investigate this hypothesis, we will first examine whether AAV-mediated overexpression of IkBm in CST neurons will enhance regeneration of injured CST axons into a neural stem cell (NSC) graft following SCI. We have found that limited numbers of injured CST fibers spontaneously regenerate into NSC graft tissue placed in a site of SCI..........
