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Title: Investigating histone deacetylase four in sensory neurons
Author: Crow, Megan
ISNI:       0000 0004 5350 048X
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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Histone deacetylase inhibitors are analgesic in preclinical pain models but the contribution of specific histone deacetylases (HDACs) to pain states remains unclear. HDAC4 is a transcriptional co-repressor that has previously been linked to aberrant nociception and synaptic plasticity. The aim of this project was to investigate the role of HDAC4 in vivo using the Cre-loxP system to conditionally delete HDAC4 from primary sensory neurons and characterize transcriptional and behavioural outcomes in models of pain and peripheral nerve regeneration. To do this I established two novel HDAC4 conditional knockout strains that enabled investigation of HDAC4 in both sensory neuron development and in adult sensory processing. In both strains, loss of HDAC4 was associated with altered expression of the gene encoding the transient receptor potential cation channel member A1 (Trpa1) and the voltage-gated calcium channel subunit α2δ-1 (Cacna2d1) in naïve ganglia. Bioinformatics analysis indicated that HDAC4 may bind Cacna2d1 directly. Furthermore, across many injury paradigms I found that HDAC4 conditional knockouts expressed lower levels of calcitonin-related polypeptide alpha (Calca) and the gene encoding the high-affinity nerve growth factor receptor (Ntrk1). While peripheral expression of HDAC4 was not required for sensory neuron differentiation, peripheral nerve regeneration or for the development of mechanical hypersensitivity in neuropathic pain models, I found highly reproducible and significant attenuation of thermal hypersensitivity in models of chronic inflammation. This was associated with significantly reduced mRNA expression of the transient receptor potential cation channel member V1 (Trpv1) and reduced capsaicin sensitivity in vitro, possibly as a result of aberrant nerve growth factor signaling. HDAC inhibitors and other drugs that target chromatin modifying and transcriptional regulatory proteins are already being used clinically to treat cancer. Work to characterize the function of these molecules in diverse systems will provide a rational basis for the broader application of these therapies.
Supervisor: McMahon, Stephen Brendan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available