Date of Award

10-31-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Retinal microglia activation and function is a pivotal component of ocular disease pathology, but their involvement in diabetic retinopathy, a complex neurovascular complication of diabetes, remains unclear. The purpose of this thesis work is to thoroughly examine features of microglia activation in DR, identify mechanistic underpinnings of their contributions to neuroinflammatory features of disease pathogenesis, and assess immunotherapeutic targeting of microglia as a potential approach to treating early-stage DR. Here, we show that chronic hyperglycemia elicits morphological, ultrastructural, and transcriptional changes in retinal microglia during early-stage DR while other elements of the retinal neurovascular unit remain unperturbed. Through chronic ablation of retinal microglia in diabetic mice, we find that microglia are not only first responders to chronic hyperglycemia but also potent contributors to visual dysfunction and neurodegeneration. Furthermore, we find that microglia are particularly detrimental to amacrine cells, a critical interneuron subtype, through aberrant contact and phagocytosis. Through ligand-receptor analysis of DR-associated microglial transcriptomic changes, we discover that microglia upregulate CD200R while its immunomodulatory cognate protein CD200, is decreased in amacrine cells of the diabetic retina, and correlates with retinal inflammation and pathological microglial contact. Lastly, we find that CD200-CD200R dysregulation is amenable to treatment via CD200 fusion protein (CD200Fc), which attenuates high glucose-induced inflammation, transcriptomic changes, and phagocytosis in microglia in vitro. Furthermore, we show that CD200Fc suppresses visual dysfunction, microglia activation, and retinal inflammation in the STZ mouse in vivo, demonstrating that CD200Fc treatment may be a promising therapeutic avenue for preventing microglia-mediated retinopathy in diabetic animals and patients. Together, these findings show that microglia are a significant contributor to features of early-stage DR and are amenable to treatment via correction of CD200-CD200R dysregulation in vivo. This work provides a valuable framework for future studies in microglia-mediated disease pathology as well as development of this novel therapy in the context of DR.

Language

English (en)

Chair and Committee

Rajendra Apte

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