Glaucoma is a very common age-related neurodegenerative disease characterized by the death of the retinal
ganglion cells. Despite its prevalence, there are no neuroprotective treatments for glaucoma. The only current
treatment is lowering intraocular pressure which unfortunately does not prevent or restore vision loss in many
patients. Due to extensive research in both glaucoma patients and animal models of glaucoma, much is known
about glaucomatous neurodegeneration, both at the physiological and molecular levels. However, despite this,
we still lack a molecular understanding of the early pathological events that injure RGCs as a result of ocular
hypertension. Microglia cells are a major component of the neuroinflammatory response in neurodegenerative
diseases and after injury to the central nervous system. In fact, microglia cell response is thought to play key
roles in many neurodegenerative diseases, including, Alzheimer’s disease, Parkinson’s disease, Huntingtin
disease, and Amyotrophic Lateral Sclerosis. Work in other systems has shown that microglia can act be both
protective and detrimental in the disease process, and possibly these two actions could take place sequentially
in the same disease. Recent studies using modern sequencing technology has shown that microglia exist in
different molecular states which correspond to their role in disease. A major, well-supported hypothesis in
glaucoma research is that microglial cells are critical for maintaining retinal ganglion cell viability after a
glaucomatous insult. However, the importance of microglia in an ocular hypertensive model of glaucoma has not
been critically tested. In this application we propose to test the hypothesis that different activated states of
microglia play distinct roles in glaucoma dependent upon stage of disease. Specifically, in two ocular
hypertensive glaucoma mouse models, we will: (1) Determine if the role of microglia activation varies with
disease stage, (2) define and test the importance of different molecular states, and (3) determine the role of
microglial derived neurotoxic cytokines. Overall, this proposal we will define novel mechanisms by which
microglia states modulate glaucoma onset and progression leading to novel candidates for therapeutic
evaluation.