# Regulation of Detrusor Overactivity by Cellular Stress in Bladder Ischemia

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2021 · —

## Abstract

The overall goal of this renewal research proposal is to determine the role of ischemia in the development of
detrusor overactivity in the non-obstructed bladder. Another goal is to examine the efficacy of targeting cellular
stress response pathways to prevent or reverse bladder dysfunction. Lower urinary tract symptoms (LUTS) are
bothersome constellation of voiding symptoms with significant impact on quality of life. The prevalence of
bladder dysfunction and LUTS among Veterans is almost five folds higher in comparison with its incidence in
the general population. It was shown that Veterans with LUTS had a worse quality of life score than Veterans
without LUTS. In most cases, particularly in elderly Veterans, LUTS resulted in insomnia, anxiety, fatigue, and
depression. Most cases of LUTS in male are attributed to bladder outlet obstruction (BOO) due to benign
prostatic enlargement (BPE). However, it has been shown that in approximately one third to more than one half
of cases, LUTS are not associated with BPE or BOO. These observations suggest that, in addition to BOO,
aging-related local changes in the bladder contribute to LUTS. Growing evidence from basic and clinical
research suggests that aging-associated bladder ischemia play a key role. Impairment of human bladder blood
flow and the development of bladder ischemia have been verified in elderly patients with LUTS. However, the
underlying mechanisms contributing to detrusor overactivity in bladder ischemia remain largely unknown. Our
preliminary data suggest that ischemia provokes cellular stress and compromises cellular defensive capacity
by impairing the cellular energy sensor adenosine monophosphate-activated protein kinase alpha-2 (AMPK-
α2). Cell stress and defective AMPK-α2 give rise to a unique stress response RNA with two complementary
strands namely double-stranded RNA (dsRNA) leading to activation of the AMPK-α2/dsRNA stress response
pathway. The AMPK-α2/dsRNA pathway seems to compromise muscarinic M2 and M3 receptors, provoke
post-translational modifications of contractile proteins, increase smooth muscle contractions and engender
detrusor overactivity. We hypothesize that “chronic ischemia is an independent factor in the development of
detrusor overactivity in the non-obstructed bladder. The mechanism involves activation of cellular stress
response via AMPK-α2/dsRNA pathway that triggers overactive bladder contractions by modification of smooth
muscle contractile elements”. Using a well-established bladder ischemia model along with knockout mice and
cell culture transfection and gene deletion technologies, we propose three specific aims. In aim I, we will define
molecular regulation of the AMPK-α2/dsRNA stress response pathway in bladder ischemia. We will determine
the mechanism of AMPK-α2 impairment, quantify and clone dsRNA in bladder ischemia and define crosstalk
mechanisms between AMPK-α2 and dsRNA. In aim II, we will define regulation of overactive contractions by
AMPK-α2/d...

## Key facts

- **NIH application ID:** 10200663
- **Project number:** 5I01BX004372-03
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** KAZEM M AZADZOI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200663

## Citation

> US National Institutes of Health, RePORTER application 10200663, Regulation of Detrusor Overactivity by Cellular Stress in Bladder Ischemia (5I01BX004372-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10200663. Licensed CC0.

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