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Glucocorticoids, ocular hypertension and glaucoma

Award Number: R01EY030967
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Glucocorticoids, ocular hypertension and glaucoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $557,079 )
2024	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	5	8/28/2024	NON-COMPETING CONTINUATION	$557,079
														Subtotal = $557,079

Issue Date FY: 2023 ( Subtotal = $557,079 )
2023	2023	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	4	8/28/2023	NON-COMPETING CONTINUATION	$557,079
														Subtotal = $557,079

Issue Date FY: 2022 ( Subtotal = $540,367 )
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	3	8/1/2022	NON-COMPETING CONTINUATION	$540,367
														Subtotal = $540,367

Issue Date FY: 2021 ( Subtotal = $540,366 )
2021	2021	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	2	8/12/2021	NON-COMPETING CONTINUATION	$540,366
														Subtotal = $540,366

Issue Date FY: 2020 ( Subtotal = $558,974 )
2020	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	1	9/11/2020	NEW	$558,974
														Subtotal = $558,974

Grand Total All Awards = $2,753,865

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Glucocorticoids, ocular hypertension and glaucoma

Award Number: R01EY030967

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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