Molecular Determinants of Critical Period in Peripheral Nerve Regeneration

The failure of regeneration after proximal peripheral nerve (PN) injury causes a catastrophic loss of motor and sensory function. This in turn results in a decreased quality of life for patient and an enormous economic burden to society. There is, therefore, an urgent need to develop new therapeutic interventions for this, and other injuries to the central nervous system (CNS).Our PN connect our brain and spinal cord to the rest of our body, controlling all volitional muscle movements. However, they are fragile and very easily damaged. Injuries of PN induce a loss of motor neural control of target organs. PN can regenerate after injury, and if the site of damage is close to the muscle controlled by the damaged nerve, full muscle function is frequently restored (distal nerve injury). In contrast, if the site of damage is far from the muscle controlled by the damaged nerve (proximal nerve injury) or injury involves complete transection of PN, recovery of muscle function is minimal.How to improve function recovery in proximal PN injury? Researchers and clinicians believe that by increasing the speed of axonal regrow, one can achieve better functional recovery. Therefore, studies in the past decades focus on enhancing the rate of axonal regeneration despite the fact that minimal function recovery has been reported. Why?We have performed a study to address this and identified a growth-associated gene, a small heat shock protein 27, accelerated intrinsic axonal growth and greatly enhance motor function recovery. Further studies showed that there is a “critical period” in mice and humans - if accelerated axons fail to reach the muscle within the critical period, no reinnervations and function recovery will occur. It seems to be a very basic concept but it explains the failure of motor recovery. This major finding initiates new research efforts in understanding how to delay critical period and possibly overcome it, in order to achieve return of motor function.In current proposed study, we aim to address directly, what molecular determinants are necessary for critical period. We will perform a major screening to determine what key molecules favor growth of regenerating axon during critical period and test these molecules in animal model of critical period. We will also examine the unexplored protective effects of Hsp27 on CNS neuron to see if increase intrinsic growth of these axotomized neurons will give them the capacity to regrow.