The Role of Müller Glia in Acute and Chronic Response to Stress, Injury, and Disease in the Retina

PROJECT SUMMARY Tissues respond to stress, injury, and disease through a process called inflammation, which involves the activation of the immune system, repair of tissues, and removal of cellular debris. Inflammation can be acute and last for several days or chronic and last for several months to years. In the retina, acute inflammation is often associated with bacterial or viral infection (e.g., uveitis), and chronic inflammation occurs in retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy. Inflammation is often neuroprotective, but under some circumstances, it can accelerate retinal disease progression and vision loss. Multiple cell types participate in the acute and chronic inflammatory processes in the eye; these cells include astrocytes, microglia, Müller glia, immune cells, vascular endothelial cells, and retinal pigment epithelia. For simplicity, researchers often focus on a single cell type in a particular disease process (e.g., microglia in age-related macular degeneration), and they use short-term acute injuries (e.g., light damage or N-methyl-D-aspartate) to gain insights into chronic inflammation in retinal disease. Thus, a major gap in our knowledge is the role of each cell type across diverse stress, injury, and disease conditions. To address this gap, we have spent the last 3 years developing a detailed profile of the acute inflammatory response in human and mouse retinae to 15 physiologically relevant cellular perturbations; those data are in the Acute Retinal Stress Interactive Portal (ARS-IP). We have also profiled 12 genetic mouse models of human retinopathy, and those data are in the murine Retinal Disease Database (mRD-Db). All unpublished data from the ARS-IP and mRD-Db are freely shared through the St. Jude Cloud. The most exciting discoveries we have made by integrating the ARS-IP and mRD-Db data are that Müller glia play a central role in coordinating the inflammatory response and distinct pathways are activated during acute versus chronic retinal inflammation. Therefore, we are uniquely positioned to investigate the interplay between acute and chronic inflammation in retinal disease. This proposal is focused on Müller glia, but we will profile all retinal cell types and share unpublished data through the St. Jude Cloud to accelerate discoveries in other cell populations that contribute to retinal inflammation. This research proposal is relevant to human health, as it will provide a deeper understanding of the molecular and cellular mechanisms that maintain retinal homeostasis and how those mechanisms are disrupted during acute and chronic disease conditions that are directly relevant to human blindness.