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Title: Investigating the pathogenesis of congenital insensitivity to pain using gene-editing in an in vitro model
Author: McDermott, Lucy A.
ISNI:       0000 0004 8502 9063
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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The voltage gated sodium channel Nav1.7 is a key component of the mammalian nociceptive system. Homozygous loss of function mutations in SCN9A, the gene that encodes Nav1.7, cause congenital insensitivity to pain (CIP) in humans. Affected individuals are unable to perceive pain in response to any noxious stimulus, be it mechanical, chemical or thermal in form. Rare Mendelian disorders such as CIP can offer insight into the complexities of common, polygenic conditions such as chronic pain. As a result, the channel has attracted significant interest as a therapeutic and research target. However, a lack of primary material suitable for studying human Nav1.7 has hindered the characterisation of its function and cellular localisation. Here, we have developed an in vitro human model through the use of gene-editing tools suitable for the experimental interrogation of hNav1.7. Using CRISPR/Cas9, we genetically tag Nav1.7 and reveal the channel is robustly expressed at the soma cell surface, axons and enriched in the terminals of iPSC-nociceptors. Further, through the use of both novel gene-edited and CIP derived lines we demonstrate the channel has a key role in regulating neuronal excitability. Together, our findings provide mechanistic insight into the pathogenesis of congenital insensitivity to pain and contribute, more broadly, to our understanding of human nociceptive signalling.
Supervisor: Bennett, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available