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

项目概要/摘要 膀胱控制丧失是脊髓损伤患者面临的最具挑战性的结果之一， 目前没有药物治疗。长期以来，神经生长因子一直与 脊髓损伤（SCI）后膀胱功能障碍。SCI后以及膀胱过度活动症和间质性 膀胱炎/膀胱疼痛综合征，在尿中检测到NGF水平的增加。的增加 尿中的NGF与膀胱超敏反应有关，许多人试图中和NGF，但 结果好坏参半。在中枢神经系统损伤或癫痫发作后，我们发现proNGF，而不是 成熟的神经生长因子，在啮齿动物和人类的脊髓损伤后迅速释放到尿液中。这些结果 提示脊髓损伤后选择性释放proNGF可能是哺乳动物的共同特征， 类似的角色。 我们在小鼠中的研究显示，proNGF在CNS和膀胱中均起作用：阻断proNGF 与穿过血脑/脊髓的小分子LM 11 A-31系统性结合p75 有效的屏障，导致反射性排尿的显著改善。反射亢进减弱 膀胱压力正常，比对照组提前数周获得自发排尿。的 改善伴随着膀胱腔表面的保护，通常 脊髓损伤后出现大量细胞丢失，随后出现增生和逼尿肌肥大。另 另一方面，当通过条件性删除尿路上皮细胞中的p75而局部阻断proNGF与p75的结合时， 脊髓损伤后膀胱功能恶化，尽管伞细胞的丢失被完全阻止。由于我们 数据表明，伞细胞的死亡完全是由于尿proNGF激活p75， 管腔表面，这些结果表明，伞细胞的损失和随后的尿路上皮营业额 积极影响排尿功能。因此，我们假设proNGF-p75信号在 SCI后膀胱功能在膀胱回路和周围。在这个假设下，我们 建议确定p75诱导SCI后尿道上皮更新的机制， 尿路上皮p75影响排尿，以及在膀胱回路中，proNGF-p75信号传导作用于 影响SCI后膀胱功能。

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.