Dataset Information

Multi-omics analysis of the bladder and its sensitivity to inosine in a rat model of spinal cord injury

ABSTRACT: This study investigates the molecular changes in the bladder following spinal cord injury (SCI) in rats and the impact of inosine treatment using a multi-omics approach. We discovered the activation of PARP (Poly(ADP-ribose) polymerase) in response to SCI, a previously unrecognized phenomenon, and its attenuation with inosine treatment. SCI triggered significant DNA damage and oxidative stress pathways, whereas inosine treatment prevents DNA damage and inhibits PARP activation, offering a potential therapeutic avenue. The integrated analysis of transcriptomics and proteomics data revealed concordant regulation of multiple pathways following SCI, including EIF2 signaling and NRF2-mediated oxidative stress response, which are ameliorated by inosine treatment. These findings have relevance to human neurogenic bladder pathobiology. Pathway inhibition by inosine in the setting of SCI suggests its potential for neuroprotection in the bladder. Despite limitations, such as the focus on male rats and a lack of proteomics data from separated detrusor and mucosa, this study provides valuable insights into the molecular mechanisms underlying bladder dysfunction following SCI. It also suggests the repurposing of FDA-approved PARP inhibitors for the treatment of bladder dysfunction following spinal injury.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Urinary Bladder

SUBMITTER: Wei Yang

LAB HEAD: Wei Yang

PROVIDER: PXD046096 | Pride | 2025-07-14

REPOSITORIES: Pride

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Multiomics analysis unveils an inosine-sensitive DNA damage response in neurogenic bladder after spinal cord injury.

Hashemi Gheinani Ali A Sack Bryan S BS Bigger-Allen Alexander A Thaker Hatim H Atta Hussein H Lambrinos George G Costa Kyle K Doyle Claire C Gharaee-Kermani Mehrnaz M Patalano Susan S Piper Mary M Cotellessa Justin F JF Vitko Dijana D Li Haiying H Kadayil Prabhakaran Manubhai M Cristofaro Vivian V Froehlich John J Lee Richard S RS Yang Wei W Sullivan Maryrose P MP Macoska Jill A JA Adam Rosalyn M RM

JCI insight 20250508 12

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. Canonica ...[more]

PMID: 40338665

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Project description:T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T-cell deficient athymic nude (AN) rats recover better than immunocompetent Sprague-Dawley (SD) rats following spinal cord transection. In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery. AN rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for Th2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue. 2x2 model with 4 groups and 12 total samples. 2 rat strains (athymic nude [AN] and Sprague-Dawley [SD]) and 2 time points (1 week post-injury [acute] and 8 weeks post-injury [chronic]). 3 samples per group, for a total of 12 samples. No technical replicates were performed. Acute SD group = rats 618, 619, and 620. Chronic SD group = rats 605, 606, and 608. Acute AN group = rats 714, 715, and 717. Chronic AN group = rats 707, 712, and 713.

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