Project Summary
It is estimated that 18 million people worldwide are legally blind from optic neuropathies such as advanced glaucoma.
Restoration of vision requires regenerating the optic nerve, a collection of retinal ganglion cell (RGC) axons that have
exited the eye to connect with the brain. Although promising, cell transplantation-based strategies alone are inadequate to
regenerate the optic nerve, in part, because transplanted RGCs fail to extend an axon out of the eye. Similarly, neuro-
regenerative approaches are limited by failure to direct long distance axon growth. In this project, I propose an innovative
approach that uses applied electrical fields (EFs) to guide RGC axon growth. Recently, I have demonstrated that RGC
axons grow directionally, towards the cathode, when exposed to an EF, in vitro. Whether EFs can direct RGC axon
growth in vivo, is unknown, as are the mechanisms through which cells sense and respond to EFs. Preliminary data
presented here shows that 1) an EF can be generated along the rat optic nerve, 2) in vivo application of EFs promotes
RGC axon regeneration after crush injury, and 3) co-activation of Rac1, a member of the Rho GTPase family,
synergistically directs RGC axon growth in vitro. This proposal aims to demonstrate the feasibility of in vivo EF
application as a therapeutic modality to guide RGC axon regeneration and test the hypothesis that EFs direct RGC axon
regeneration by activating the Rho-GTPase signaling cascade. The K08 Career Development Award will provide me with
structured education in research methodology, applied electrical engineering and electrophysiology, and technology
transfer as well as structured mentorship to fill in educational and experiential gaps in knowledge, develop skills in
leadership, work life balance, and grant and manuscript writing that will allow me to transition to an independent, NIH-
funded clinician-scientist who is a world expert in the field of optic nerve regeneration. I have strategically assembled a
mentorship team consisting of electrical engineers, material scientists, electrophysiologists, cell biologists, neurosurgeons,
neurobiologists, statisticians, and translational scientists to complement my background as a neuro-ophthalmologist and
developmental neurobiologist and direct my learning and career trajectory. Successful completion of this project will
position me to become a competitive R01 applicant where I plan to test whether EF application, in conjunction with
molecular cues, can be used to direct axon growth of transplanted RGCs to regenerate the optic nerve and restore visual
function in different animal models of optic neuropathies. If successful, this project has the potential to make large strides
in the field of optic nerve regeneration, bringing electrical modulation to the forefront.