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.