RETROGRADE INJURY SIGNALING AND CYTOSKELETAL ALTERATIONS IN BARREL CORTEX AFTER TBI

TBI may cause axonal damage at a site that is far away from the cell body of a neuron where the nucleus is located. In peripheral neurons, several signaling molecules form complex with the microtubule motor, cytoplasmic dynein upon axonal injury. Dynein transports these factors retrogradely to the cell body, and this retrograde injury signaling process will eventually initiate transcription in the nucleus, which is implicated in regeneration. The factors that bind to dynein upon injury include: (1) importin beta (for importing proteins into the nucleus), which is locally translated from mRNA upon injury; (2) a soluble form of vimentin, an intermediate filament protein that may serve as a scaffold for binding of other proteins; (3) JNK (C-Jun-N-terminal kinase), which is locally activated upon injury; (4) MAP kinases (Erk1 and Erk2), which become phosphorylated upon injury. The interaction between JNK or Erks and dynein/dynactin is required for regeneration. These studies suggest that dynein plays a central role in retrograde injury signaling, and that experimentally; dynein can be used as bait for fishing out proteins required for retrograde injury signaling in peripheral neurons. However, it is not clear whether neurons in the central nervous system (CNS) respond to injury in a similar fashion. We proposed to do a proteomic screen to identify proteins that bind to dynein upon CCI injury in the barrel cortex. We hope to use this novel approach to identify signaling molecules that transmit the injury signals to the nucleus and hope to be eventually able to manipulate the signals to enhance regeneration.