Thursday, November 21, 2024
11/21/2024
Glucocorticoids (GCs) are commonly used anti-inflammatory and immunosuppressive therapeutic agents for a plethora of diseases and conditions. Over 1% of our population receives GC prescriptions annually. Despite the very broad and potent anti-inflammatory effects, prolonged GC therapy can cause serious side effects, including damage to the eye. Between 30-75% of individuals receiving prolonged GC therapy develop GC- induced ocular hypertension (OHT), which if unrecognized can lead to iatrogenic open-angle glaucoma and permanent vision loss. Despite recognition of this significant GC side effect for more than six decades, we still do not understand the reason for differences in susceptibility to GC-induced OHT or the mechanism(s) of action responsible for GC-OHT. We have previously shown that the alternative spliced dominant negative isoform of the glucocorticoid receptor (GRb) inhibits GC activity in cultured human TM cells. TM cells isolated from glaucoma donor eyes (GTM) have low GRb levels and are therefore more sensitive to GCs. Although a number of studies have examined the DEX-induced transcriptome in TM cells and tissues, there is no indication which of the differentially expressed genes or molecular pathways are involved in GC-OHT. Several studies have shown that susceptibility to develop GC-OHT is genetically inherited, but no genes have been definitively linked to GC-OHT. Our overall hypothesis is that GC-OHT is: (a) determined by the ratio of endogenous GRa to GRb expression in the TM; (b) mediated by specific molecular pathways that can be differentiated from GC-responder and non-responder eyes; and (c) genetically determined so that GC-OHT genes can be mapped and identified. This overall hypothesis will be tested in 3 specific aims. Specific Aim #1: Determine the role of endogenous GRb in regulating GC-OHT in human anterior segment ex vivo perfusion culture and in vivo in mice. Specific Aim #2: Determine the TM transcriptome in GC-OHT resistant and sensitive strains of mice and in anterior segment perfusion cultured human eyes in order to identify the molecular pathways that are responsible for GC-OHT. Specific Aim #3: Map and identify the genes responsible for GC-OHT using QTL of the BXD recombinant inbred mouse lines. This research is innovative in that we will evaluate the role of endogenous GRb in mouse strains (with our new mouse model of GC-OHT) and in ex vivo perfusion cultured human anterior segments that differ in sensitivity to GC-OHT, use mouse strains and human perfusion cultured anterior segments that are differentially responsive to GC-OHT to molecularly dissect the pathway responsible for GC-OHT, and map GC-OHT genes using BXD recombinant inbred mice. This work is essential and significant because our experimental results will help determine the role of endogenous GRb in regulating responsiveness to GC-OHT, the molecular mechanisms responsible for GC-OHT, and the best and most effective way to predict steroid responders, which still is an important unmet clinical need as GC-OHT is becoming increasingly prevalent.
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