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Transcriptomic Assessment Of The P53 Signaling Pathway In The Burn Wound Zone Of Stasis
Gaurav Garg, Abdulnaser Alkhalil, Bonnie Carney, Robert Smith, Kyle Monger, Lauren Moffatt, Jeffrey Shupp.
The Burn Center, MedStar Washington Hospital Center, Washington, DC, USA.

This study was designed to characterize transcriptomic changes induced in the p53 pathway by burn injury to understand burn wound conversion and guide development of therapies to improve tissue salvage and reduce the need for excision and grafting. Brass combs heated to 100°C were used to generate 4 burns intercalated with 3 unburned interspaces on the dorsum of 10 rats. Contact time was varied to create different wound depths. Interspaces were biopsied at 3, 6, 12, 24, and 48 hours post-injury for comparison to pre-burn skin. Laser doppler imaging (LDI) was used to identify burn wound conversion. Following mRNA isolation, p53 pathway PCR arrays were used to capture transcript-level changes in 84 genes in the interspace tissues over time. The fold change in expression of each gene was determined, and a Z-score was calculated to assess overall pathway regulation. Analysis of deep partial-thickness wounds revealed induction of the p53 pathway at hour 6 (Z-score 0.853, p<0.0001) followed by downregulation at hour 48 (Z-score -1.606, p<0.0001). LDI confirmed conversion in full-thickness wounds, which had less perfusion compared to superficial partial-thickness wounds (baseline: p>0.05, all other timepoints: p<0.05). Superficial partial-thickness wounds showed downregulation and upregulation of Esr1 and IL-6, respectively, from hours 6-24, followed by upregulation of genes for cell survival (Birc5), cell cycle progression (Ccnb1, Ccne1, Cdk4), and DNA repair (Brca1, Chek1/2, Msh2, Pcna). In full-thickness wounds, multiple genes differentially regulated at hour 6 remained so until hour 48. Upregulation of Rprm and Cdkn1a/Cdkn2a with downregulation of Ppm1d indicated cell cycle arrest. This coincided with induction of pro-apoptotic Tnf and Tnfrsf10b and downregulation of DNA repair (Lig4). Downregulation of Stat1 and Egfr suggested a decrease in downstream transcription of numerous factors impacting cellular viability. Following this first examination of alterations in the p53 pathway in the burn wound zone of stasis, further investigation will focus on proteomic changes to identify potential therapeutic targets.


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