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Molecular and Cellular Correlates of Nerve Repair in Humans

ABSTRACT:

This is a longitudinal prospective cohort study in patients with carpal tunnel syndrome undergoing decompression surgery. Phenotypic data and skin biopsies were collected before and 6 months after surgery to determine molecular and cellular correlates associated with neural regeneration and neuropathic pain. RNA sequencing was performed in the skin samples and differential gene expression was determined post compared to pre surgery. The molecular changes identified in skin were correlated with the clinical phenotype representing neural regeneration.

PROVIDER: phs001796 | dbGaP |

REPOSITORIES: dbGaP

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Project description:Acute postsurgerical pain and it's management represent a major clinical challenge. In particular, severe and prolonged pain impairs immediate recovery and might lead to long-term consequences like chronic pain, opioid abuse, and reduced quality of life. Rodent incision models greatly contributed to the understanding of cutaneous wound repair, but the underlying mechanisms' knowledge remains incomplete, yet translational data are urgently needed to develop novel treatment options and preventive measures. We combined extensive sensory phenotyping with unbiased quantitative proteomics in human and mouse skin after an incision to assess interspecies protein signatures to overcome this gap. Additionally, stratification of human volunteers based on the hyperalgesic area after surgery in correlation with the corresponding proteomic fingerprint revealed novel insides into human-specific mechanisms.Unbiased skin proteome analysis of both species unveiled comparable protein signatures after incision, notably for inflammatory activity and actin polymerization. Upon incision, we could discern 50 commonly regulated proteins, amounting to 61% of all regulated human and 10% regulated mouse proteins. Notably, the direction of regulation upon incision, i.e. up-or downregulated, was conserved in humans and mice to a great extent. Integrative analysis of pain-related phenotyping with quantitative mass spectrometry identified hitherto unknown skin protein signatures, providing a tool for stratification on the protein level. Protein-protein interaction (PPI)-networks differed between volunteers with small incision-related hyperalgesic areas (termed"low responder") versus those with large areas ("high responder"). In particular, PPIs of volunteers exhibiting a large hyperalgesic area were characterized by a predominant dysregulated proteolytic environment associated with persistent inflammation reponse. In contrast, PPI- networks of low responders point to anti-inflammatory processes. Here, we present a framework for specific-specific alterations in human and mice upon incision, highlighting similarities and differences on a protein network level. Moreover, the detection of developing hyperalgesia and pain after surgery in volunteers and it's correlation with corresponding molecular fingerprints indicates the need for tailored treatments to prevent chronification processes in humans after surgery.

Dataset Information

Molecular and Cellular Correlates of Nerve Repair in Humans

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