Harnessing intrinsic stress responses for neuroprotection and repair

Axons are critical for communication throughout the nervous system, and axonal damage is a common feature of many neurological conditions, ranging from traumatic injuries (spinal cord injury, traumatic brain injury, peripheral nerve injury) to neurodegenerative diseases (glaucoma, ALS, etc.). The response of neurons to axonal stress is a major determinant of their fates. Activation of complex programs for repair can result in axon regeneration and remarkable recovery of function in the PNS. But these programs are linked with stress responses that can become major drivers of neurodegeneration in the CNS. Understanding intrinsic stress signaling my therefore guide new approaches for promoting the survival and reconnection of diseased and damaged neurons.

Research interests in the Watkins Lab include:

Unraveling the pathways that lead to neurodegeneration and axon regeneration. Using models of CNS and PNS axon injury, we have uncovered substantial commonality, as well as some critical differences, between the stress signaling pathways that lead to neuronal death in one environment and repair in the other. What additional pathways influence neuronal survival and recovery?

Determining the outcomes of axonal injury signaling. Stress responses to axon damage simultaneously prime neurons for axon regeneration and neurodegeneration, though they do not alone dictate the distressed neuron's fate. What determines the ultimate outcome of those responses? How might we modify the environment to encourage repair?

Deciphering the transcription factor combinatorial code that determines the fates of injured neurons. Axonal injury signaling results in extensive changes to the transcriptome through the activation of multiple stress-responsive transcription factors. The genomic targets of these transcription factors are dependent on the various combinations of these factors. How does this combinatorial code direct the fates of distressed neurons?