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

proNGF-p75 信号在脊髓损伤后膀胱控制中的作用

• 批准号: 10360573
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 51.77万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360573
• 关键词: Address; Apoptosis; Apoptotic; Attenuated; Binding; Biology; Bladder; Bladder Control; Bladder Dysfunction; Blocking Antibodies; Blood; Brain; C Fiber; Capsaicin; Cells; Cessation of life; Commissure; Complement; Data; Development; Dorsal; Exhibits; FOS gene; Functional disorder; Glutamates; Human; Hyperplasia; Hyperreflexia; Hypersensitivity; Hypertrophy; Injury; Interstitial Cystitis; Intravesical Instillation; Knockout Mice; Mammals; Micturition Reflex; Motor; Mus; Natural regeneration; Neurons; Outcome; Overactive Bladder; Pharmacotherapy; Phase; Phenotype; Play; Proliferating; Reflex action; Rodent; Role; Seizures; Signal Transduction; Site; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Surface; Synapses; Time; Tyrosine 3-Monooxygenase; Urination; Urine; Urothelial Cell; Urothelium; conditional knockout; mouse genetics; preservation; pressure; prevent; progenitor; receptor; small molecule; small molecule inhibitor; stem cell proliferation; transcriptional coactivator p75; urinary; urologic

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.

项目摘要/摘要 失去膀胱控制是脊髓受伤患者面临的最具挑战性的结果之一， 目前没有药物治疗。 NGF长期以来一直与 脊髓损伤（SCI）后膀胱功能障碍。 SCI以及过度活跃的膀胱和间隙之后 膀胱炎/疼痛膀胱综合征，尿液中检测到NGF水平的升高。随着增加 在尿液中，NGF与膀胱超敏反应有关，许多人试图中和NGF，但与 混合的结果。就像在受伤或癫痫发作后的中枢神经系统中一样，我们发现了Prongf，而不是 成熟的NGF在啮齿动物和人类中SCI后迅速释放到尿液中。这些结果 建议在SCI之后的选择性释放PRONGF可能是哺乳动物中的共同特征 一个类似的角色。 我们在小鼠中的研究表明，prongf在中枢神经系统和膀胱中都作用：阻止prongf 与小分子LM11A-31系统地结合P75，该分子穿过血脑/脊髓 有效地屏障，导致反射空隙的急剧改善。超反射症被衰减 在正常的膀胱压力下，比对照比对照提前几周获得自发性空隙。这 改进伴随着保存膀胱腔表面，通常 经历了大规模的细胞损失，然后在SCI后发生增生和逆肥力。另一方面 手，当prongf与p75结合时，通过在尿路上皮细胞中有条件删除p75局部阻塞时， SCI后，膀胱功能恶化，尽管完全阻止了伞状细胞损失。自从我们 数据表明，伞状细胞的死亡完全是由于尿液prongf激活了p75 腔表面，这些结果表明雨伞细胞的丧失和随后的尿路周转率 积极影响空隙功能。因此，我们假设PRONGF-P75信号在 SCI之后的膀胱功能在膀胱电路和外围。在假设下，我们 提议确定p75在SCI之后诱导尿路上皮的周转的机制， 尿路上皮p75会影响空隙，以及在膀胱电路中，Prongf-P75信号的作用 影响SCI后膀胱功能。