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Integrated omics analysis unveils a DNA damage response to neurogenic injury.
Gheinani, Ali Hashemi; Sack, Bryan S; Bigger-Allen, Alex; Thaker, Hatim; Atta, Hussein; Lambrinos, George; Costa, Kyle; Doyle, Claire; Gharaee-Kermani, Mehrnaz; Patalano, Susan; Piper, Mary; Cotellessa, Justin F; Vitko, Dijana; Li, Haiying; Prabhakaran, Manubhai Kadayil; Cristofaro, Vivian; Froehlich, John; Lee, Richard S; Yang, Wei; Sullivan, Maryrose P; Macoska, Jill A; Adam, Rosalyn M.
Afiliación
  • Gheinani AH; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Sack BS; Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Switzerland.
  • Bigger-Allen A; Department of Urology, Inselspital University Hospital, 3010 Bern, Switzerland.
  • Thaker H; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Atta H; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lambrinos G; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Costa K; Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Switzerland.
  • Doyle C; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Gharaee-Kermani M; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Patalano S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Piper M; Biological & Biomedical Sciences Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, MA.
  • Cotellessa JF; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Vitko D; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Li H; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Prabhakaran MK; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Cristofaro V; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Froehlich J; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Lee RS; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Yang W; Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
  • Sullivan MP; Department of Surgery, Harvard Medical School, Boston, MA, USA.
  • Macoska JA; University of Massachusetts, Boston, MA, USA.
  • Adam RM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
bioRxiv ; 2023 Dec 10.
Article en En | MEDLINE | ID: mdl-38106029
ABSTRACT
Spinal cord injury (SCI) evokes profound bladder dysfunction. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed systemic inosine treatment improved bladder function following SCI in rats. Here, we applied multi-omics analysis to explore molecular alterations in the bladder and their sensitivity to inosine following SCI. Canonical pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator analysis identified MYC as a key regulator, whereas causal network analysis predicted multiple regulators of DNA damage response signaling following injury, including PARP-1. Staining for both DNA damage (γH2AX) and PARP activity (poly-ADP-ribose) markers in the bladder was increased following SCI, and attenuated in inosine-treated tissues. 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 novel insights into the molecular landscape of the bladder following SCI, and highlight a potential role for PARP inhibition to treat neurogenic bladder dysfunction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos