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Nox Enzymes in Aging Bladder Dysfunction

Award Number: R01AG049321
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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Nox Enzymes in Aging Bladder Dysfunction - DESCRIPTION (provided by applicant): Specific Aim 1. To identify the enzymatic sources of ROS generation and Nox expression in the urothelial and bladder tissues at different ages (young vs. middle-aged and aging) in experimental animals (mice) and humans. This aim will identify the origin of ROS and specific contribution from Nox enzymes, and then the expression of the Nox in the urothelium and smooth muscle, and the age dependence. These form the basis for the action of Nox-derived ROS in the bladder. 1. Major sources for ROS generation in urothelium and smooth muscle (NADPH oxidases; mitochondria; other oxidases/oxygenases) 2. Expression and activity of Nox2 (prototype) and other Nox isoforms (Nox1, Nox4) in urothelium and smooth muscle 3. Age-dependent changes to ROS generation and Nox activities. Specific Aim 2. To determine age-associated Nox activation in urothelium and consequent oxidative stress damage of bladder function at different ages using wild-type and Nox knockout mice. This aim will define Nox activation in the urothelium in response to the inflammatory factors encountered during aging, its consequent action on urothelial and smooth muscle function and the underlying mechanisms. 1. To identify the changes in urothelial Nox activity in response to inflammatory stimuli in young versus middle-aged and aging bladders 2. To characterize the effects of Nox activation on urothelial ATP release and smooth muscle contractions in young versus aging bladders 3. To discover the key signaling mediators and proteins in aging-dependent Nox activation in urothelial and bladder tissues. Specific Aim 3. To investigate the cellular mechanisms of redox-regulation in urothelial function using primary urothelial cells isolated from wild-type versus Nox knockout mice at different ages. This aim will explore further the cellular mechanisms of ROS/Nox regulation and their interaction with the key pathways for aging and bladder function, providing fundamental mechanisms for Nox contribution to bladder dysfunction during aging. 1. Effect of different ROS enzyme inhibitors and ROS scavengers on urothelial cell release of ATP and other sensory mediators. 2. Changes in urothelial Nox activity in response to inflammatory stimuli. Focus on the stress pathway. 3. Effects of ROS (H2O2) at different levels on urothelial ATP release and calcium release. 4. Importance of ROS for downstream intracellular signaling pathways in the regulation of urothelial transmitter release - role of intracellular Ca2+, exocytosis, chloride channels, kinases and connexins.


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: 2023 ( Subtotal = $0 )
2023	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	5	9/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	5	6/14/2022	NON-COMPETING CONTINUATION	$0
2022	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	5	12/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $441,432 )
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	5	11/27/2019	NON-COMPETING CONTINUATION	$397,289
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	5	1/22/2020	NON-COMPETING CONTINUATION	$44,143
														Subtotal = $441,432

Issue Date FY: 2019 ( Subtotal = $470,920 )
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	4	12/24/2018	NON-COMPETING CONTINUATION	$470,920
														Subtotal = $470,920

Issue Date FY: 2018 ( Subtotal = $269,077 )
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	3	12/15/2017	NON-COMPETING CONTINUATION	$242,169
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	3	4/13/2018	NON-COMPETING CONTINUATION	$26,908
														Subtotal = $269,077

Issue Date FY: 2017 ( Subtotal = $269,077 )
2017	2017	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	2	12/27/2016	NON-COMPETING CONTINUATION	$242,169
2017	2017	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	2	6/20/2017	NON-COMPETING CONTINUATION	$26,908
														Subtotal = $269,077

Issue Date FY: 2016 ( Subtotal = $257,326 )
2016	2016	TEMPLE UNIVERSITY	BROAD & MONTGOMERY AVENUE	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	1	2/3/2016	NEW	$257,326
														Subtotal = $257,326

Grand Total All Awards = $1,707,832

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Nox Enzymes in Aging Bladder Dysfunction

Award Number: R01AG049321

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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