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Title: Epidermal growth factor receptor ligands as modulators of peripheral nerve injury
Author: Kiesewetter, Hannes
ISNI:       0000 0004 5350 0877
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2014
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Signalling between different cell types in the nervous system is a key element in the pathophysiology of peripheral nerve injury. Epidermal growth factor receptor ligands (EGFRLs) bind the EGF receptor (ErbB1) and its related protein ErbB4 forming an adaptable signalling system implicated in multiple biological processes. Ligands binding the EGF receptor have not yet been implicated in the pathophysiology of nerve injury. In this thesis, I demonstrated differential expression of EGFR ligands following nerve injury in rats, such as Amphiregulin, Epidermal growth factor, Epiregulin, Heparin-binding EGF, Transforming growth factor-α and Betacellulin (BTC). In a medium-throughput quantitative PCR array screening of cytokines, BTC was one of the top differentially upregulated factors following partial sciatic nerve transection (SNT) at different timepoints. Given that its role in the nervous system is unknown I set out to elucidate its mechanism of action following injury. First I examined its ability to activate intracellular pathways. Although BTC activated ERK and p38 MAP kinases in relevant cell types (dorsal root ganglion neurons, macrophages) imaging experiments indicated no change in intracellular calcium levels. To investigate a potential neuronal effect I examined the growth promoting effect of BTC on dissociated DRG neurons. The growth factor did not affect neurite outgrowth. Interestingly, other EGFR ligands were also ineffective. In cultured peritoneal macrophages chemotaxis was not affected in vitro, but I demonstrated a chemotactic effect in vivo. Additionally, examination of a panel of macrophage phenotypic markers revealed a downregulation of the phagocytic scavenger receptor CD36 following stimulation with BTC. Intrathecal injection of BTC in the spinal cord (L4-L5), was able to activate ERK but did not affect thermal (Hargreaves) and mechanical (von Frey) sensitivity. Moreover, blocking the EGF receptor in models of either inflammatory (formalin injection in the hindpaw) or neuropathic (SNT) pain did not alter thermal and mechanical hypersensitivity. In summary, BTC is robustly upregulated following peripheral nerve injury. Although its role its not yet completely clarified, my data points towards a modulating effect on the macrophage phenotype and its an interesting target for future investigation on the pathophysiology of nerve injury.
Supervisor: McMahon, Stephen Brendan; Bennett, David Laurence Harvey Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available