Protein Signatures of Incision Injury in Humans and Mice - a Translational Study

by Christin Kappert
Cumulative thesis
Date of Examination:2022-06-21
Date of issue:2024-05-08
Advisor:Prof. Dr. Manuela Schmidt
Referee:Prof. Dr. Manuela Schmidt
Referee:Prof. Dr. Henning Urlaub
Referee:Prof. Dr. Walter Paulus
Referee:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Dr. Juliane Liepe
Persistent Address: http://dx.doi.org/10.53846/goediss-10461

 

 

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Abstract

English

Acute pain is the physiological reaction of a body to noxious external stimuli such as surgical interventions. Depending on the intensity and persistence of pain, tissue recovery may be hampered leading to post-operative complications. Treatment options are still sub-optimal due to incomplete knowledge about the underlying mechanisms. Pre-clinical models in rodents helped to gain insides into physiological and pathophysiological processes upon incision injury but failed to understand the full molecular landscape and functional alterations in humans. Thus, bidirectional translational studies in humans and mice are indispensable to close the translational gap. In order to identify mechanistically relevant proteins of incision injury, we used an experimental incision model in humans and mice followed by label-free liquid chromatography mass spectrometry (LC-MS) analysis of skin biopsies. The proteomic signatures were analysed on a network-based level to identify: i) key candidates in humans and mice, and ii) those with high translational potential, i.e. being shared across species. However, morphological and molecular differences between species, as well as the heterogeneity of human pain phenotypes present major challenges in biomedical research. To account for pain-related phenotypes in humans, the pathophysiological parameter of hyperalgesia (HA) was used to stratify volunteers post-surgically into high (large HA) and low (small HA) responders. Repeated proteomic analysis of responder types resulted in distinct signatures. While high responders exhibited a strong influence of the immune system, proteins in low responders were annotated to anti-inflammatory and remodeling processes. Prolonged inflammatory processes may explain the elevated pain perception in high responders after surgery. Interestingly, comparable results were obtained in blood plasma at baseline. Therefore, I hypothesize that pain after surgery is independent of the procedure but rather has intrinsic factors that favor the outcome. From a clinical point of view, those prognostic markers can serve as valuable targets for tailored pain treatment to prevent chronic pain.
Keywords: Mass Spectrometry; Proteomics; Incision Injury; Skin; Blood; Incisional Pain; Carry-over; DIA-MS/MS; Hyperalgesic Area; Human; Mouse
 
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