All ETDs from UAB

Advisory Committee Chair

Marina Gorbatyuk

Advisory Committee Members

Alecia K Gross

Timothy W Garvey

Machelle Pardue

Maria B Grant

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) School of Optometry

Abstract

Diabetic retinopathy (DR) is reported to be one of the leading causes of blindness in the United States by Center for Disease Prevention and Control. As the estimated prevalence of the disease will likely triple by 2020, the research in this area should focus on identifying novel targets and therapeutic approaches. One of the therapeutic approaches for DR is the reprograming of retinal metabolism to delay the progression of the disease. The unfolded protein response (UPR) is recognized as a cellular pathway activated in diabetic retina which interacts with key transcription factors to physiologically regulate glucose, lipid homeostasis, and angiogenic signaling. During development and progression of DR, persistent activation of UPR occurs. Tribbles homologous 3 (TRIB3) is one of the UPR mediators activated in response to stress. My current project is focused on exploring TRIB3 protein as a novel therapeutic target for DR treatment. We hypothesize that TRIB3 is elevated in diabetic retina leading to aberrant insulin signaling and neovascularization. We tested this hypothesis in animal models of STZ-induced diabetes and hypoxia-induced proliferative retinopathy. Moreover, we identified the mechanism of TRIB3-mediated progression of DR in primary cultured retinal Muller cells. Our data demonstrated that TRIB3 controls major molecular events in early diabetic retinas. It specifically, regulates a retinal glucose flux, and alters expression of inflammatory and metabolic markers. In addition, we found that TRIB3 ablation leads to significant retinal ganglion cell (RGC) survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation in hyperglycemic retinas. In hypoxic conditions, TRIB3 KO retinas significantly diminished GFAP and VEGF expression, thus regulating gliosis and aberrant vascularization, and preserving retinal integrity. In conclusion, overexpression of TRIB3 in hyperglycemic and hypoxic retinas may accelerate the onset and progression of DR to proliferative stages indicating TRIB3 as a potential therapeutic target.

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Optometry Commons

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