Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells. While it is unclear how retinal ganglion cells are injured in glaucoma, there are considerable data supporting axonal injury as an early, critical insult in glaucoma. In fact, it is thought that retinal ganglion cell axons are injured as they exit the eye through a specialized structure called the lamina cribrosa. Despite knowing the likely location of the glaucomatous insult, the earliest pathological responses to ocular hypertension within retinal ganglion cells are undefined. It is perhaps not surprising that these events have been difficult to define because the pathological responses are likely activated only transiently, in a small region of the axon (as they travel through the lamina), and only in a subset of axons at any given time. We and others have shown that after an axonal insult, distinct molecular pathways control degeneration of different retinal ganglion cell compartments. However, we do not know how a very local axonal injury response irreversibly activates somal and axonal degenerative programs. Here, we describe experiments that will define the molecular pathways controlling and linking the compartmentalized response of retinal ganglion cells to an ocular hypertensive insult. Our central hypothesis is that ocular hypertension activates axonal injury signaling pathways that regulate compartment-specific degeneration processes, and inhibiting these processes will prevent glaucomatous neurodegeneration. To test this hypothesis, we will perturb these pathways in ocular hypertensive models of glaucoma and assess the effects on somal and axonal degeneration. Furthermore, we will examine how inhibiting these pathways alters key aspects of retinal ganglion cell injury response, including axonal transport and retinal ganglion cell function. Also, we will define the transcriptomic changes within retinal ganglion cells that contribute to ocular hypertension- induced retinal ganglion cell death. Overall these experiments will provide an integrated understanding of the pathological signaling that controls glaucomatous neurodegeneration. Given the importance of axonal insult and axonal degeneration in glaucoma, these experiments will likely identify novel targets for developing neuroprotective treatments for glaucoma.