Hashemi Gheinani Ali, Sack Bryan S, Bigger-Allen Alexander, Thaker Hatim, Atta Hussein, Lambrinos George, Costa Kyle, Doyle Claire, Gharaee-Kermani Mehrnaz, Patalano Susan, Piper Mary, Cotellessa Justin F, Vitko Dijana, Li Haiying, Kadayil Prabhakaran Manubhai, Cristofaro Vivian, Froehlich John, Lee Richard S, Yang Wei, Sullivan Maryrose P, Macoska Jill A, Adam Rosalyn M
Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Switzerland.
JCI Insight. 2025 May 8;10(12). doi: 10.1172/jci.insight.180275. eCollection 2025 Jun 23.
Spinal cord injury (SCI) evokes profound dysfunction in hollow organs such as the urinary bladder and gut. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed that systemic treatment with the neuroprotective agent inosine improved bladder function following SCI in rats. Here, we applied integrated multi-omics analysis to explore molecular alterations in the bladder over time and their sensitivity to inosine following SCI. Canonical signaling pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator and causal network analysis predicted multiple effectors of DNA damage response signaling following injury, including poly-ADP ribose phosphorylase-1 (PARP1). Markers of DNA damage (γH2AX, ATM/ATR substrates) and PARP activity were increased in bladder tissue following SCI and attenuated with inosine treatment. Inosine treatment also attenuated oxidative DNA damage in rat bladder cells in vitro. Proteomics analysis suggested that SCI induced changes in protein synthesis-, neuroplasticity-, and oxidative stress-associated pathways, a subset of which were shown in transcriptomics data to be inosine sensitive. These findings provide insights into the molecular landscape of the bladder following SCI and identify key inosine-sensitive pathways associated with injury.
脊髓损伤（SCI）会引发膀胱和肠道等中空器官的严重功能障碍。目前的治疗方法因缺乏分子数据来指导新的治疗途径而受到限制。此前，我们表明用神经保护剂肌苷进行全身治疗可改善大鼠脊髓损伤后的膀胱功能。在此，我们应用综合多组学分析来探究脊髓损伤后膀胱随时间的分子变化及其对肌苷的敏感性。脊髓损伤调控的典型信号通路包括与蛋白质合成、神经可塑性、伤口愈合和神经递质降解相关的通路。上游调节因子和因果网络分析预测了损伤后DNA损伤反应信号的多个效应器，包括聚ADP核糖磷酸化酶-1（PARP1）。脊髓损伤后膀胱组织中DNA损伤标志物（γH2AX、ATM/ATR底物）和PARP活性增加，而肌苷治疗可使其减弱。肌苷治疗还可减轻体外培养的大鼠膀胱细胞中的氧化性DNA损伤。蛋白质组学分析表明，脊髓损伤诱导了与蛋白质合成、神经可塑性和氧化应激相关通路的变化，转录组学数据显示其中一部分通路对肌苷敏感。这些发现为脊髓损伤后膀胱的分子格局提供了见解，并确定了与损伤相关的关键肌苷敏感通路。
