Friday, May 9, 2025
5/9/2025
Retinal circuit integration and degeneration in Neurofibromatosis type-1 - PROJECT SUMMARY In optic glioma, including that associated with Neurofibromatosis type-1 (NF1), retinal ganglion cells (RGCs) sustain axon injury, and patients often lose vision in early life. Damage to RGC axons in the optic nerve, whether compressive, traumatic, ischemic, or degenerative, results in an irreversible loss of vision due to the inability of RGCs to remain viable and regenerate their axons. NF1 occurs in every 1 in 3000 children. Glioma formation in the optic nerve often results in the loss of visual acuity in young children, and the only available treatment is chemotherapy, which has less than 30% success rate. Therefore, strategies that can provide RGC protection prior to injury and therapies that can replace lost cells are needed. One potential treatment showing high promise is cell transplantation therapy. However, most of this data was developed in acute trauma models of optic nerve crush, which may or may not translate to the axon damage and retinal and optic nerve environment in NF1 optic glioma. Furthermore, it is unclear if transplanted cells could harm the remaining circuitry in the retina. In the first part of this proposal, the candidate will evaluate the functional impact of RGC loss during the progression of NF1. They will also evaluate donor RGC transplantation’s impact on the remaining intact retinal circuitry. For the second part of this proposal, they will examine if transplanted RGCs can be encouraged to form functional connections within the retina when their activity is synchronized with the host retina. The candidate’s career goal is to obtain a tenured faculty position in neurosciences studying neural regeneration in models of optic neuropathy. They aim to develop an independent research group to address how newly transplanted RGCs can integrate successfully into the visual circuit pathway. The candidate has previous experience in retinal circuitry, behavioral assessment, and functional imaging in explanted tissue. In this proposal, they aim to 1) acquire the technical knowledge and skillset necessary to examine cell replacement therapy in an animal model of NF1, 2) learn the techniques to evaluate functional visual outcomes over time in vivo, 3) develop as a manager and leader to prepare for an independent faculty position. During the mentored phase of this award, the candidate will prioritize undertaking activities to increase understanding of glioma formation and vision loss in NF1, to do productive and meaningful science, and consequently to transition evaluating visual outcomes in vivo and correlating those with morphological changes. The PI will work with mentors Dr. Jeffrey Goldberg and Dr. David Gutmann and members of a Stanford faculty advisory team. The proposed research and training plans will occur in Dr. Jeffrey Goldberg’s laboratory, the Blumenkranz Smead Professor and Chair of the Byers Eye Institute Department of Ophthalmology at Stanford University. The outstanding vision science group at Stanford is embedded within the world-class neuroscience and broader life sciences community at Stanford as a whole, with the benefits of a close-knit and focused department and the resources of the wider university.
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