Monday, October 27, 2025 10/27/2025

Role of Urothelial Purinergic Signaling in Diabetic Bladder Dysfunction

Award Number: R01DK119482
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: 01/09/2020
PERIOD OF PERFORMANCE END DATE: 09/14/2028

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Role of Urothelial Purinergic Signaling in Diabetic Bladder Dysfunction - PROJECT SUMMARY/ABSTRACT Despite the high prevalence of Western diet-associated diseases and their clear impact on numerous systems in the body, we know very little about the origin and mechanisms of bladder dysfunction in type 2 diabetes. Current treatment strategies, although partially effective, target mainly the contractility of detrusor muscle, and have numerous unfavorable off target side effects. We propose to study cellular and molecular mechanisms of extracellular purinergic signaling in the bladder urothelium and suburothelium/lamina propria (LP) in bladder dysfunctions of two mouse models of type 2 diabetes (T2D) with obesity. We will build on four important advances made during the initial award, such as discovery of (i) mechanosensitive degradation of ATP at the luminal and abluminal sides of the urothelium, (ii) urothelial release of soluble ectonucleotidases (s-ENTDs), (iii) differential distribution of s-ENTDs in LP and lumen, and (iv) regulation of s-ENTDs release by various membrane channels, sensory neuropeptides, and receptors. In pilot studies, db/db diabetic mice and mice with T2D and obesity induced by high-fat high-sucrose diet (HFHSD-T2D) developed enlarged and underactive bladders, accompanied by extreme ATP and ADP decrease and prominent adenosine increase in the LP but not in the lumen. Such observations lay the foundation for the present proposal, aimed at identifying probable causes for severe purine disbalance in the LP of the diabetic bladder that are likely linked to considerable voiding dysfunctions. In Aim 1, we will perform comprehensive assessments of (i) voiding functions and (ii) purine availability in LP and lumen during bladder filling in control and T2D mice. Aim 2 will determine (i) the role of s- ENTDs in accelerated hydrolysis of ATP causing increased formation of adenosine in the LP of the diabetic bladders, (ii) contribution of the AC-cAMP-AMPK signaling in s-ENTDs release, and (iii) distribution and cellular sources of s-ENTDs in the bladder wall. Aim 3 will define the roles of equilibrative nucleoside transporters ENT1 and ENT2 in disproportionate accumulation of adenosine in the LP of the diabetic bladder by investigating alterations of transmembrane and transurothelial nucleoside transport and cellular localization of ENTs. We will use an interdisciplinary approach, including analytical chemistry, protein biochemistry, and molecular biology techniques and genetic tools; in vivo and ex vivo evaluation of bladder function; and sonographic imaging in nondiabetic and diabetic mice and mice with specific gene deletions. Key mechanisms of ATP hydrolysis by s- ENTDs and regulation of their mechanosensitive release will be validated in bladders of Cynomolgus monkeys (Macaca fascicularis) to translate findings in mice to primate biology. The proposed preclinical, discovery- oriented research will advance our understanding of molecular mechanisms regulating availability of the biologically active adenyl purines ATP, ADP, and adenosine at their cellular and receptor targets in the bladder wall. This work has the potential to serve as foundational research for the development of novel therapeutics that could influence or prevent the development of bladder dysfunctions associated with T2D and obesity.


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 = $310,683 )
2025	2025	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/15/2025	COMPETING CONTINUATION	$311,224
2025	2023	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/14/2025	NON-COMPETING CONTINUATION	-$541
														Subtotal = $310,683

Issue Date FY: 2023 ( Subtotal = $583,548 )
2023	2023	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/16/2023	NON-COMPETING CONTINUATION	$583,548
														Subtotal = $583,548

Issue Date FY: 2022 ( Subtotal = $583,548 )
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/19/2022	NON-COMPETING CONTINUATION	$58,357
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/7/2022	NON-COMPETING CONTINUATION	$525,191
														Subtotal = $583,548

Issue Date FY: 2021 ( Subtotal = $583,548 )
2021	2021	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/4/2021	NON-COMPETING CONTINUATION	$583,548
														Subtotal = $583,548

Issue Date FY: 2020 ( Subtotal = $583,548 )
2020	2020	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/9/2020	NEW	$583,548
														Subtotal = $583,548

Grand Total All Awards = $2,644,875

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Role of Urothelial Purinergic Signaling in Diabetic Bladder Dysfunction

Award Number: R01DK119482

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: 01/09/2020

PERIOD OF PERFORMANCE END DATE: 09/14/2028

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