# Role of proNGF-p75 signaling in the bladder control after spinal cord injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $518,716

## Abstract

PROJECT SUMMARY/ABSTRACT
Loss of bladder control is one of the most challenging outcomes facing spinal cord injured patients, with
no drug treatments available at the present time. NGF has long been implicated in the development of
bladder dysfunction after spinal cord injury (SCI). After SCI as well as in overactive bladder and interstitial
cystitis/painful bladder syndromes, an increase in NGF levels is detected in the urine. As the increase
in urinary NGF is implicated in bladder hypersensitivity, many have tried to neutralize NGF, but with
mixed results. As in the CNS after injury or seizure, we have discovered that proNGF, and not
mature NGF, is rapidly released into the urine after SCI in rodents as well as in humans. These results
suggest that selective release of proNGF right after SCI may be a common feature in mammals, playing
an analogous role.
Our study in mice revealed that proNGF acts both in the CNS and in the bladder: Blocking proNGF
binding to p75 systemically with a small molecule, LM11A-31, that crosses the blood-brain/spinal cord
barrier efficiently, resulted in dramatic improvement in reflex voiding. The hyperreflexia was attenuated
with normal bladder pressure, acquiring spontaneous voiding weeks earlier than the control. The
improvement was accompanied by preservation of the bladder luminal surface, which normally
undergoes massive cell loss followed by hyperplasia and detrusor hypertrophy after SCI. On the other
hand, when proNGF binding to p75 was blocked locally by conditionally deleting p75 in urothelial cells,
bladder function worsened after SCI, although umbrella cell loss was completely prevented. Since our
data indicate that the death of umbrella cells is entirely due to urinary proNGF activating p75 on the
luminal surface, these results suggest that the loss of umbrella cells and subsequent urothelial turnover
influence voiding function positively. We thus hypothesize that that proNGF-p75 signaling plays a role in
bladder function after SCI both in the bladder circuit and in the periphery. Under the hypothesis, we
propose to determine the mechanism by which p75 induces the turnover of the urothelium after SCI,
urothelial p75 influences voiding, and where in the bladder circuitry that proNGF-p75 signaling acts to
influences bladder function after SCI.

## Key facts

- **NIH application ID:** 9875460
- **Project number:** 5R01DK120108-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** MARGARET Ann VIZZARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,716
- **Award type:** 5
- **Project period:** 2019-02-18 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875460

## Citation

> US National Institutes of Health, RePORTER application 9875460, Role of proNGF-p75 signaling in the bladder control after spinal cord injury (5R01DK120108-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875460. Licensed CC0.

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