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Title: The role of p11 (S100A10) in nociception
Author: Foulkes, T.
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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The S100-family protein p11 (S100A10) is involved in a variety of physiological processes, including channel trafficking and angiogenesis. In this thesis, we used genetic approaches to investigate the functional roles of p11. p11 modulates the plasma membrane trafficking of the sensory neuron-specific voltage-gated Na" channel Nay 1.8 and numerous other proteins. Since Nav1.8 performs a specialised function in the detection of noxious stimuli (nociception), we investigated the role of p11 in peripheral pain pathways. We used the Ctq-IoxP system to delete p11 exclusively from nociceptive neurons, allowing the examination of this aspect of p11 function without confounding effects from roles of p11 in other tissues, p11-null neurons showed deficits in the functional expression of Nav1.8. Noxious coding in wide-dynamic range neurons in the dorsal horn was compromised in p11-null animals. Acute mechanical pain behaviour was attenuated, but no deficits in inflammatory pain were observed. Reduced neuropathic pain behaviour was apparent in nociceptor-specific p11-null mice. While certain effects of p11 deletion can be explained by reduced Nav1.8 trafficking. Nav1.8 is not required for neuropathic pain, p11 therefore acts through both Nay1.8-dependent and alternative mechanisms to control nociceptive thresholds. This suggests it is a potential therapeutic target. Given the importance of p11-dependent modulation of Nav1.8. we investigated the p11-binding site on the Nav1.8 N-terminus. In vitro fluorescence resonance energy transfer (FRET) assays were used to examine this interaction. In contrast to previous studies, we found the interaction to be complex, involving two distinct binding sites and an autoinhibitory domain. The p11-Nav1.8 interaction is therefore not well-suited to small molecule-based inhibition. p11 has been reported to play an important role in processes required for angiogenesis. In assays of angiogenesis-dependent tumour growth, global p11 deletion resulted in increased tumour volume and altered vascular morphology. This may have implications for novel anti-cancer therapies targeting p11.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available