Dissecting the complex role of microglia states in glaucoma

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.