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Caveolae-Based Mechanosensors for Conventional Outflow Regulation

Award Number: R01EY028608
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Caveolae-Based Mechanosensors for Conventional Outflow Regulation - Project summary Glaucoma is the second leading cause of blindness worldwide with primary open angle glaucoma (POAG) being the most prevalent form. The primary risk factor for POAG, elevated intraocular pressure (IOP), results from pathology in the conventional outflow pathway. The IOP-dependent mechanical responsiveness of the conventional outflow tissue is critical to the homeostatic maintenance of IOP in the normal range, however, the mechanosensors and their transduction pathways, are not well-understood. In this project, we will examine one mechanical sensor, caveolae, which we have found to play important roles in outflow cell contractile processes. Gene variants at the CAV1/2 genes, which encode the essential proteins for caveolae formation, reproducibly associate with POAG and, importantly, with IOP elevation. Ablation of CAV1 both globally and in outflow cell-specific contexts results in ocular hypertension and defects in aqueous humor drainage from the conventional outflow pathway. The cell-intrinsic mechanisms by which caveolae transduce responses to IOP fluctuations and the connection between CAV1/2 gene variants not understood and this project expands on our prior work to address these gaps in our understanding. We hypothesize that outflow pathway caveolae are mechanosensitive/mechanoprotective platforms that transduce changes in IOP in the trabecular meshwork, the Schlemm’s canal, and in the distal outlow pathway vasculature to dynamically regulate aqueous humor drainage and thereby modulate IOP. We also predict that POAG-associated CAV1/2 risk variants impact the mechanically-induced transcriptional program to build caveolae. The successful completion of these studies has clear


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: 2025 ( Subtotal = $604,777 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	6	3/13/2025	NON-COMPETING CONTINUATION	$604,777
														Subtotal = $604,777

Issue Date FY: 2024 ( Subtotal = $615,971 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	001	5	2/14/2024	COMPETING CONTINUATION	$615,972
2024	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	4	1/19/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = $615,971

Issue Date FY: 2021 ( Subtotal = $478,171 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	4	6/14/2021	NON-COMPETING CONTINUATION	$478,171
														Subtotal = $478,171

Issue Date FY: 2020 ( Subtotal = $486,926 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	3	6/8/2020	NON-COMPETING CONTINUATION	$486,926
														Subtotal = $486,926

Issue Date FY: 2019 ( Subtotal = $488,047 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	2	6/26/2019	NON-COMPETING CONTINUATION	$488,047
														Subtotal = $488,047

Issue Date FY: 2018 ( Subtotal = $498,565 )
2018	2018	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	1	8/29/2018	NEW	$498,565
														Subtotal = $498,565

Grand Total All Awards = $3,172,457

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Caveolae-Based Mechanosensors for Conventional Outflow Regulation

Award Number: R01EY028608

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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