Identifying Factors that Protect Ganglion Cells from Death After Optic Nerve Injury
During glaucoma, retinal ganglion cell (RGC) axons are damaged and this causes the RGCs to die, ultimately resulting in the irreversible loss of visual function. Currently, there are no FDA-approved drugs or therapies to protect RGCs from death in glaucoma. Experiments in this proposal utilize the zebrafish as a model system, leveraging its unique biology where RGCs do not die when their axons are damaged, even in extreme cases when the optic nerve is completely severed. By understanding how zebrafish RGCs survive after axonal damage we will uncover novel modes of neuroprotection that could ultimately be translated into new targets for neuroprotection to preserve RGCs in glaucoma patients.
Glaucoma is a neurodegenerative disease that affects ~64 million people, with a predicted rise to of 111 million people world-wide by 2040. During glaucoma, retinal ganglion cell (RGC) axons are damaged and this causes the RGCs to die. As these are the key cells in the eye that convey visual information to the brain, when they die, this inevitably results in the irreversible loss of visual function. Currently, there are no FDA-approved drugs or therapies to protect RGCs from death in glaucoma. This is a major barrier in the field and one that must be addressed given the predicted rise in glaucoma incidence over the next 20 years. Our overarching goal is to identify novel therapies that can protect RGCs from death during glaucoma. Here, we utilize the zebrafish as an innovative discovery platform through which we can identify genes and pathways that protect RGCs after axonal injury. Zebrafish are an ideal model for this research because almost all RGCs survive, even when the optic nerve is completely cut, indicating that they possess remarkable protective strategies to keep RGCs alive after injury. Here, we leverage this unique biology of zebrafish to address two main goals. Goal 1: We will identify genes and molecular pathways that protect RGCs from injury induced death and we will determine how these genes and pathways enable RGCs to survive. The major outcome here will be a list of novel candidates that can be further developed into potential therapies to preserve RGCs in early stage glaucoma. Goal 2: We will examine a linkage between activity of the immune system and inflammation as key factors in modulating RGC survival. We will directly assess immune system activation and determine how it affects RGC survival after injury. The major outcome here will be a direct assessment of the functional relevance of immune system activity after optic nerve injury and identification of candidate immune-derived factors that could function to protect RGCs after injury. When completed, the results of this study will be significant to the field by providing a list of factors that can be screened for efficacy in mammals, potentially serving as the foundation for the development of novel protective strategies that are effective in keeping RGCs alive in the earliest stages of glaucoma.