microRNAs and other small RNAs generated by the ribonuclease Dicer are involved in a variety of physiological processes including immune responses, neuronal function and modulation of synaptic plasticity. This thesis uses the Nav1.8-Cre mouse to ablate Dicer in post-mitotic nociceptors, in order to study the role of small RNAs in nociception. Colleagues have previously identified that loss of small RNAs within these nociceptors leads to deficits in inflammatory pain behaviour, and that the expression of nociceptor transcripts is greatly reduced. In this thesis electrophysiological recordings were used. It was determined that Dicer null nociceptors were not capable of being sensitised using inflammatory mediators. This was found to be due to reduced functional voltage gated sodium channel expression, particularly Nav1.8 and Nav1.9, leading to impaired action potential electrogenesis and loss of repetitive firing properties. Deep sequencing and bioinformatic analysis were used to identify the miRNA and small RNA repertoire in dorsal root ganglia (DRG) tissue. Additionally, nociceptor enriched miRNAs were identified using the conditional Dicer knockout mouse. The observation that the loss of miRNAs leads to reduced expression of nociceptor transcripts does not fit with the canonical RNA interference (RNAi) paradigm. Therefore a hypothesis that small RNAs can induce transcription was tested using bioinformatic approaches and functional studies in DRG neurons.
|Publisher||University College London (University of London)|
|Source Sets||Ethos UK|
|Type||Electronic Thesis or Dissertation|
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