kimberly gokoffski - US grants

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.

Despite enormous advances in recent years to develop neuroprosthetics to bypass damaged areas of the Central Nervous System (CNS), these devices fail to halt the progression of the underlying degenerative diseases for which they were designed. Moreover, there are no effective therapies for many of the neurodegenerative conditions that affect, for example, the eye or the brain, and the humanitarian and economic impact of blinding diseases and dementia are enormous, with underrepresented groups particularly impacted by these conditions. The goal of this project is to enable restoration of function to the CNS by therapies that promote the repair and regeneration of damaged neurons and neural networks instead of bypassing damaged areas. To achieve this goal of delaying vision loss and neural degeneration in dementia through devices this team brings together engineers, surgeons, neuroscientists and big data/imaging scientists.

This research team will devise and optimize, experimentally and computationally, the electrical stimulation waveform characteristics needed to reprogram damaged neural network morphologies; create, “first of its kind” complete mesoscale connectivity atlases of the global neural networks exposed to electric fields and field gradients; develop predictive multiscale computational models of neural activity in healthy, degenerated and electrically stimulated neural networks; and design and engineer programmable implantable electronic systems for the acute neurostimulation of the neural tissue. The utility of the tools developed in the proposed effort will be enhanced by end-users providing design input, thus facilitating fully integrated, mutually beneficial, sustained convergent collaborations that are needed to develop the therapeutic opportunities of the next generation.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.