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TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction

Award Number: R01DK119615
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/19/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction - SUMMARY Stress-induced bladder dysfunction (SIBD) in children can manifest as overactive bladder (OAB) or underactive bladder/incomplete bladder emptying (UAB). Bladder dysfunction affects children medically, socially, emotionally and behaviorally; yet treatment options are limited and often ineffective. Recently, we have implicated transient receptor potential vanilloid family type1 (TRPV1) channels in the pathophysiology of adult OAB, but their roles in SIBD are unknown. Juvenile mice subjected to social stress developed OAB or UAB, depending on the intensity and duration of the stress. When social stress caused overactivity, TRPV1-mediated bladder afferent activity increased that was wholly absent in unstressed mice. When social stress caused underactivity, afferent activity was unchanged, but bladders were significantly remodeled and decompensated. Interestingly, TRPV1-KO mice developed no SIBD or any kind, regardless of the intensity or duration of social stress. Thus, Thus, we hypothesize that SIBD is progressive, such that (1) stress increases TRPV1-dependent afferent nerve activity, leading to bladder overactivity; (2) these aberrant signals to the central nervous system (CNS) coupled with bladder overactivity itself result in bladder remodeling; and (3) this remodeling decreases bladder compliance, afferent outflow and muscle contractility, leading to underactivity and ultimately urinary retention. This proposal will mechanistically investigate the onset and progression of SIBD through our unique murine model of stress-induced bladder dysfunction, which closely models pediatric bladder pathology. In this proposal, we will investigate how the duration/intensity of social stress causes bladder dysfunction and determine the role TRPV1 channels play in the progression of SIBD. We will deploy a wide array of techniques (histology, fluorescent in situ hybridization, ex vivo afferent nerve recordings, imaging, cystometry, conscious voiding behavior) and an array of transgenic and knockout mouse models to explore the pathophysiology of SIBD and determine how TRPV1 channels affect bladder function. The idea that both bladder overactivity and underactivity develop from aberrant TRPV1 channel sensitization simplifies our understanding of how stress causes bladder dysfunction and may lead to effective treatments for this debilitating condition.


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 = $343,164 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/21/2023	NON-COMPETING CONTINUATION	$343,164
														Subtotal = $343,164

Issue Date FY: 2022 ( Subtotal = $397,789 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/28/2022	NON-COMPETING CONTINUATION	$343,484
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	7/1/2022	SUPPLEMENT FOR EXPANSION	$54,305
														Subtotal = $397,789

Issue Date FY: 2021 ( Subtotal = $434,314 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/1/2021	NON-COMPETING CONTINUATION	$416,212
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/9/2021	SUPPLEMENT FOR EXPANSION	$18,102
														Subtotal = $434,314

Issue Date FY: 2020 ( Subtotal = $344,119 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/1/2020	NON-COMPETING CONTINUATION	$344,119
														Subtotal = $344,119

Issue Date FY: 2019 ( Subtotal = $365,587 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/19/2019	NEW	$363,433
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/12/2019	NEW	$2,154
														Subtotal = $365,587

Grand Total All Awards = $1,884,973

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TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction

Award Number: R01DK119615

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/19/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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