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

项目摘要/摘要 失去膀胱控制是脊髓损伤患者面临的最具挑战性的结局之一， 目前还没有药物治疗方法。长期以来，NGF一直被认为与血管生成有关 脊髓损伤(SCI)后膀胱功能障碍。脊髓损伤后以及过度活动的膀胱和间质 膀胱炎/痛性膀胱综合征时，尿液中神经生长因子水平升高。由于增加了 在尿液中，NGF与膀胱过敏有关，许多人试图中和NGF，但 结果好坏参半。就像在中枢神经损伤或癫痫发作后，我们发现proNGF，而不是 在啮齿动物和人类的脊髓损伤后，成熟的NGF迅速释放到尿液中。这些结果 提示脊髓损伤后proNGF的选择性释放可能是哺乳动物的共同特征， 一个类似的角色。 我们在小鼠身上的研究表明，proNGF在中枢神经系统和膀胱中都有作用：阻断proNGF 通过跨越血-脑/脊髓的小分子LM11A-31系统地与p75结合 有效的屏障，导致反射性排尿的显著改善。反射亢进减轻了。 膀胱压力正常，自发性排尿比对照组提前数周。这个 改善伴随着膀胱腔表面的保留，通常情况下 脊髓损伤后经历大量细胞丢失、增生和逼尿肌肥大。另一方面 另一方面，当通过有条件地删除尿路上皮细胞中的p75而局部阻断proNGF与p75的结合时， 脊髓损伤后，尽管伞状细胞丢失被完全阻止，但膀胱功能恶化。因为我们的 资料表明，伞状细胞的死亡完全是由于尿液中的ProNGF激活了p75。 管腔表面，这些结果表明伞状细胞的丢失和随后的尿路上皮更新 对排尿功能有积极影响。因此，我们假设proNGF-p75信号在 脊髓损伤后膀胱环和外周的膀胱功能。在这个假设下，我们 建议确定p75诱导脊髓损伤后尿路上皮翻转的机制， 尿路上皮p75影响排尿，以及proNGF-p75信号在膀胱回路中的作用。 影响脊髓损伤后的膀胱功能。

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.