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Impaired TRVP4-eNOS signaling in TM contributes to glaucoma

Award Number: R01EY034238
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Impaired TRVP4-eNOS signaling in TM contributes to glaucoma - Abstract Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Elevated intraocular pressure (IOP) due to dysfunction of trabecular meshwork (TM) tissue is a hallmark of POAG. However, the pathological mechanisms leading to TM dysfunction and IOP elevation are poorly understood. TM has an intrinsic ability to maintain IOP homeostasis by sensing the changes in the flow of aqueous humor (AH). In this regard, we recently showed that Ca2+ influx through transient receptor potential vanilloid 4 ion channels in the TM (TRPV4TM channels) lowers IOP via activation of endothelial nitric oxide synthase (eNOS)–NO signaling. Importantly, we showed that TRPV4TM-eNOSTM signaling is impaired in glaucomatous primary human TM cells. The major goals of this application are to elucidate the pathological mechanisms that impair TRPV4TM-eNOSTM signaling in glaucoma and to target them for rescuing the TM function. Chronic endoplasmic reticulum (ER) stress is a crucial contributor to TM dysfunction and IOP elevation in glaucoma. In our preliminary studies, we observed that chronic ER stress activates inducible NOS (iNOS), an enzyme commonly associated with the formation of oxidant molecule peroxynitrite (PN). PN levels are elevated in TM tissues from POAG donor eyes and exogenous PN reduced TRPV4TM channel activity in human primary TM cells. Moreover, induction of ER stress also lowered TRPV4TM channel activity. Therefore, we hypothesize that PN-induced inhibition of TRPV4TM-eNOSTM signaling contributes to TM dysfunction and IOP elevation in glaucoma. The major objectives of this application are to determine whether chronic ER stress leads to TM dysfunction and IOP elevation via PN-induced lowering of TRPV4TM-eNOSTM signaling in glaucoma, and to target this pathology for the treatment of glaucoma. In Aim 1, we will determine whether chronic ER stress lowers TRPV4 channel activity in TM cells. In Aim 2, we will determine whether PN levels are elevated in glaucoma and whether PN lowers TRPV4 channel activity in TM. We will also determine whether chronic ER stress underlies elevated PN levels in glaucoma. In Aim 3, we will target PN pathology to lower elevated IOP in mouse and human models of ocular hypertension. This proposal utilizes complementary expertise of Dr. Zode’s laboratory in glaucoma research and ER stress, and Dr. Sonkusare’s laboratory in TRP ion channel imaging and electrophysiology. This study will utilize state-of-art Ca2+ imaging, patch-clamp, eNOS activity, and nitric oxide measurements in primary human TM cells and TM tissues, human perfusion cultured donor eyes, and mouse models of glaucoma. Successful completion of the proposed studies will provide novel pathological mechanisms and therapeutic targets for the treatment of general POAG.


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 = $447,890 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	002	3	7/11/2024	NON-COMPETING CONTINUATION	$447,890
2024	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	2	11/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$164,479
2024	2022	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	1	11/1/2023	NEW	-$164,479
														Subtotal = $447,890

Issue Date FY: 2023 ( Subtotal = $447,890 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	2	8/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$447,890
2023	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	1	8/11/2023	NEW	$0
														Subtotal = $447,890

Issue Date FY: 2022 ( Subtotal = $444,075 )
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	1	8/22/2022	NEW	$444,075
														Subtotal = $444,075

Grand Total All Awards = $1,339,855

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Impaired TRVP4-eNOS signaling in TM contributes to glaucoma

Award Number: R01EY034238

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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