One of the barriers to therapeutic neural regeneration in humans is the absence of neural stem cells in most regions of the adult brain. Potential treatments for diseased and injured brains therefore have focused on transplantation of stem cells and their derivatives. However, transplants are complicated both by tumorigenicity and by inefficient functional integration. It therefore would be advantageous to use resident cells for regeneration. In addition, progress in the field would be accelerated if neuroregeneration from resident cells could be investigated using a genetic model organism. Toward this end, we have developed a novel injury paradigm in the adult Drosophila melanogaster central brain called Penetrating Traumatic Brain Injury (PTBI). Using the PTBI model, we have shown that, despite the absence of recognizable neural progenitors, cells in the adult Drosophila central brain proliferate following injury and that both new neurons and new glial cells are generated. Because known neural stem cells undergo terminal divisions or apoptosis prior to adulthood, our studies indicate that non-canonical neural precursor cells are present in the adult Drosophila brain, and that these precursors are capable of contributing to neuroregeneration. Our results are paradigm-shifting because they suggest that brain cells can be de-differentiated, induced to proliferate, and give rise to new neurons and glia. Furthermore, we have evidence that activation of the immune system is an early step in the regenerative process which suggests that targeted immunotherapy may be a useful therapeutic for diseased and injured brains.
It would be advantageous to be able to treat neurodegenerative diseases and brain injuries using cells resident in the brain as versus transplanted stem cells. We have developed a novel injury and neural regeneration model in the adult brain of the genetic model organism Drosophila melanogaster and are using this model to explore the molecular mechanisms underlying brain regeneration. The goal of the experiments proposed in this application is to identify signaling pathways that trigger the regenerative cascade and to identify the cells that give rise new neurons.
