Promoting axon regeneration and functional recovery after SCI

Damage of axons connecting the brain and the spinal cord is one main cause of paralysis and other functional deficits after spinal cord injury (SCI). Thus, promoting transected axons to regenerate across lesion represents an ideal strategy for re-building circuits and restoring functions. Recent studies suggested that a key reason for their regeneration failure is the diminished intrinsic regenerative capacity in adult CNS neurons. In this regard, we and others showed that deletion of PTEN, a negative regulator of mTOR, in either young or adult corticospinal neurons is able to activates their intrinsic regenerative ability, resulting in robust re-growth of transected corticospinal tract (CST) axons (1-5, 71). In translating these findings into a neural repair strategy, we have to address several important issues: (1). Even with PTEN deletion, only a portion of injured CST axons can regenerate, pointing to the need for developing more efficient approaches. Our recent studies on optic nerve injury model suggested that the intrinsic regenerative ability could be synergistically elevated by manipulating multiple signaling pathways. For example, the effects of PTEN deletion on retinal ganglion cell (RGC) axon regrowth could be further enhanced by co-deletion of SOCS3, the negative regulator of JAK/STAT pathway (6). Thus, we hypothesize that co-activation of mTOR and STAT3 might result in further enhanced CST regeneration. (2). In addition to CST, other brain-derived descending axons are also critical in regulating different aspects of spinal cord functions. However, it is unknown whether these descending axons could be coaxed to regenerate with these manipulations and what are the functional outcomes of these regenerating axons. (3). While PTEN inhibition provides a valuable manipulation for proof-of-principle studies, the biological nature of PTEN as a tumor suppressor raises safety concerns for its clinical application. Importantly, our collaborative studies with Dr. Joshua Sanes found that over-expression of osteopontin (OPN) could allow injured RGC axons to respond to growth factors (IGF1 or BDNF), resulting in mTOR activation and axon regeneration (7). OPN and these growth factors are extracellular proteins, suggesting an translatable approach of promoting mTOR activation and axon regeneration by bypassing inhibiting PTEN. In this application, we will address these questions in adult SCI models. Aim 1. To assess the effects of post-injury deletion of PTEN and/or SOCS3 on CST regeneration and functional recovery in SCI models. Aim 2. To analyze the effects of activation of mTOR and/or JAK/STAT on the regeneration of rubrospinal and reticulospinal tracts. Aim 3. To assess the effects of OPN-based strategies for promoting axon regeneration and functional recovery.