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Estrogen-Dependent Mechanisms Modulating Diabetic Bladder Dysfunction

Award Number: R01DK146866
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: 05/11/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Estrogen-Dependent Mechanisms Modulating Diabetic Bladder Dysfunction - PROJECT SUMMARY/ABSTRACT Most patients with diabetes suffer from diabetic bladder dysfunction (DBD). Symptoms vary significantly, but the most common presentation is an overactive bladder (OAB). Mitigating OAB symptoms through strict glycemic control has proven to be clinically ineffective and there are no specialized therapies to treat OAB in patients with diabetes. Until the critical need for novel precision medicine therapies is met, the clinical challenge of treating DBD will continue to escalate. A key pathology contributing to OAB symptoms in patients with diabetes is hyperinnervation of afferent nerves in the bladder urothelia. Such hyperinnervation is attributed in part to an increase in nerve growth factor (NGF). Estrogens release NGF from urothelial cells and our preliminary data demonstrate that selective activation of the novel g-protein coupled estrogen receptor (GPER) also mediates urothelial NGF release. However, there is a significant gap in knowledge regarding how diabetes dysregulates these estrogen-dependent mechanisms. The overall objective of this proposal is to determine how diabetes impacts the development and progression of OAB mediated by estrogen-dependent mechanisms in the bladder and peripheral afferent nerves innervating the bladder. Preliminary data generated in the Akita mouse model of diabetes indicates that both estrogen deprivation and GPER antagonism prevent the development of OAB in diabetic mice. Further assessment revealed that estrogen deprivation not only prevented OAB, but also prevented afferent hyperinnervation of the urothelia. We therefore hypothesize diabetes increases estrogen-mediated NGF release via activation of urothelial GPER, which thereby promotes the growth of urothelia-innervating afferent peripheral nerves, increases pelvic nerve activity, and results in OAB. We will pursue two specific aims to test our hypothesis. Aim 1: Determine the impact of diabetes on estrogen-dependent second messenger systems responsible for urothelial NGF release. Aim 2: Determine precise mechanisms by which diabetes impacts estrogen-dependent innervation of afferent peripheral nerves to the bladder during the (a) development and (b) progression of diabetes-mediated OAB. Completion of these aims will identify novel therapeutic targets which have the potential to revolutionize the clinical management of OAB attributed to diabetes. This proposal represents the next step towards our long-term goal to develop precision medicine treatments for DBD.


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: 2026 ( Subtotal = $807,282 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/12/2026	NEW	$807,282
														Subtotal = $807,282

Grand Total All Awards = $807,282

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Estrogen-Dependent Mechanisms Modulating Diabetic Bladder Dysfunction

Award Number: R01DK146866

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: 05/11/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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