Development and regeneration of retinal ganglion cells in the vertebrate retina

About This Grant

Project Summary/Abstract Vision loss is a devastating medical problem as it can lead to reduced productivity, lower quality of life, and loss of independence. Glaucoma affects over four million Americans and 76.0 million people worldwide, making it the second leading cause of irreversible blindness globally. The disease is characterized by retinal ganglion cell degeneration with consequent loss of the axons that connect the eye to the brain and progressive damage to the optic nerve. Pharmacological and surgical interventions that lower intraocular pressure can slow or even stop retinal ganglion cell degeneration. However, many patients do not seek medical attention until the disease is advanced and others continue to experience disease progression despite treatment, ultimately resulting in the widespread loss of retinal ganglion cells and profound vision loss. Unfortunately, the human retina has minimal regenerative capacity and cannot replace lost retinal ganglion cells, making vision loss in these patients permanent. The candidate’s long-term career goals are to advance our understanding of gene regulatory networks directing retinal ganglion cell differentiation during development and to apply these insights to formulate strategies for regenerating retinal ganglion cells from dormant progenitor cells in the adult retina. The proposed career development and training plans will allow the candidate to acquire further expertise in retinal development and regeneration. By learning additional cutting-edge experimental techniques, the candidate will also enhance the scientific rigor and impact of their research program. In the first specific aim, the candidate will investigate the role of transcription factor Pou2f2 in retinal ganglion cell development using conditional gene deletion, as well as gain-of-function by in vivo electroporation of postnatal progenitors. In the second and third specific aims, the candidate will perform an in vivo screen of more than 40 candidate transcription factors to identify a combination capable of reprogramming Müller glia into retinal ganglion cells. Further studies will focus on characterizing induced retinal ganglion cell morphology, laminar position, axon extension, electrophysiology and gene expression. Adaptive optics will be used to longitudinally image the reprogramming process in vivo. Lastly, the candidate will investigate survival and circuit integration of these newly generated retinal ganglion cells in mouse models of glaucoma. Because retinal ganglion cells are widely used as a model for axonal regeneration in vertebrates, these studies have broader implications for regeneration of central nervous system neurons and pathways. The candidate will conduct the proposed research in collaboration with co-mentors Dr. Yvonne Ou and Dr. Xin Duan, and the other members of the advisory committee. Experiments will take place in Rock Hall, where the candidate has dedicated laboratory space in close proximity to all collaborators. The UCSF Department of Ophthalmology is a leading center for vision science research, providing the candidate with access to NEI P30 funded core facilities and extensive university-wide resources. The candidate will also benefit from interactions with the broader neuroscience and stem cell research communities at UCSF.