This K08 application for Yvonne Ou, MD describes a five year strategy designed to enhance her research and professional skills with the career goal of becoming an independent clinical scientist advancing our understanding of the neurodegenerative mechanisms underlying glaucoma and improving its treatment. Dr. Ou completed her MD at Harvard Medical School, ophthalmology residency at the University of California, Los Angeles, and a two-year glaucoma fellowship at Duke University. The K08 award will provide Dr. Ou, now an assistant professor at the University of California, San Francisco (UCSF), with the support necessary to accomplish the following goals: 1) to conduct laboratory studies of neuronal loss in an animal model of glaucoma, with emphasis on developing new skills in cellular neurobiology, mouse genetics, and in vivo retina imaging; 2) to become expert in retinal ganglion cell (RGC) synapse and dendrite biology both through formal didactics as well as publishing and presenting in the field; 3) to develop an independent research career. Although the exact mechanisms of glaucomatous optic neuropathy are unknown, the final common pathway is RGC death. This research examines the compartmentalized neurodegeneration of RGCs in response to elevated intraocular pressure, one of the main risk factors of glaucoma. Preliminary evidence suggests that synaptic and dendritic changes may be early events in the neurodegenerative process prior to cell death. Using a laser-induced ocular hypertension mouse model, the first aim will determine RGC synapse density in both the retina and dorsal lateral geniculate nucleus (dLGN). Initial characterization demonstrates RGC post-synaptic loss in the retina and RGC pre-synaptic loss in the dLGN. Aim 2 will examine dendrite morphology longitudinally using confocal laser scanning ophthalmoscopy to image the retinas of live CB2-GFP mice, in which a subset of relatively large transient OFF-aRGCs are genetically labeled. The third aim will evaluate RGC axonal territory and synaptic density in the dLGN of axons projecting from the non- glaucomatous eye using a novel genetic tool. Key components of the career development plan include: 1) Laboratory investigations of neuronal loss in a glaucoma animal model; 2) Mentorship from a multidisciplinary group of scientists and clinical scientists with expertise in RGC biology, rodent disease models, and in vivo retina imaging; 3) Formal didactics to expand neurobiology knowledge; 4) Presentation of data in the format of supervised manuscript and grant submissions, and presentation of work at meetings; 5) Planned transition to independence including professional development. A scientific advisory and mentorship committee has been assembled to ensure progression towards independence. The career development plan will be carried out at UCSF, which provides an outstanding environment to conduct this research, including state-of-the-art facilities and a rich and supportive community of clinical scientists critical to the success of this young investigator. PUBLIC HEALTH RELEVANCE: Glaucoma, the leading cause of irreversible blindness worldwide, is a disease in which the retinal ganglion cells of the optic nerve die, leading to gradual visual field loss and eventual blindness. A major deficit in our treatment of glaucoma is that it is often initiated after there is already evidence of retinal ganglion cell death and visua field loss. Improved understanding of which parts of the retinal ganglion cell are vulnerable in glaucoma will potentially uncover novel diagnostic and therapeutic targets for glaucoma patients.