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Towards an understanding of the role of Connexin26 in breathing
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van de Wiel, Joseph (2019) Towards an understanding of the role of Connexin26 in breathing. PhD thesis, University of Warwick.
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WRAP_Theses_VandeWiel_2019.pdf - Submitted Version - Requires a PDF viewer. Download (11Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3423287~S15
Abstract
Connexin26 (Cx26) hemichannels expressed in glia at the ventral medullary surface (VMS) have been proposed to play a role in respiratory chemoreception, although this is disputed. At the VMS Cx26 hemichannels open in response to CO2 directly, causing ATP release that is capable of increasing respiratory drive. The main aim of this work was to establish a genetic strategy that can be used in vivo to elegantly remove Cx26 CO2- sensitivity from chemosensitive areas of the VMS, and to thereby investigate the role that Cx26 CO2 sensitivity plays in the chemoreception of awake mice.
Using Forster resonance energy transfer and dye loading studies a Cx26 mutant (Cx26DN) was found to coassemble with Cx26WT subunits (forming heteromeric connexon hemichannels) and to remove CO2-induced hemichannel opening from cells stably expressing Cx26WT.
In mice aged 12-18 weeks, bilateral lentivirus injections were used to express Cx26DN in GFAP+ cells at the VMS, as a means of removing CO2-induced Cx26 hemichannel opening and subsequent ATP release. As determined by whole-body plethysmography, expression of Cx26DN in the retrotrapezoid nucleus (RTN) had no effect on the hypercapnic ventilatory response in mice. Accidental Cx26DN expression in the caudal chemosensitive area resulted in reduced tidal volume 3 weeks post-transduction, however this was not well supported statistically. Such an auspicious result from suboptimal caudal expression warrants this to be repeated in order to validate these results.
The work performed in this thesis outlines the first use of a highly novel genetic tool to remove the CO2-sensitivity property of Cx26 from specific cells, without removing the protein from the system. The results shed light on our understanding of central respiratory chemoreception, suggesting that Cx26 plays no role in chemoreception in the RTN but is likely to play a role in caudal areas of the VMS. Such a tool could aid research into the virtually unexplored role that Cx26 CO2 gating has in the body.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology |
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| Library of Congress Subject Headings (LCSH): | Respiration -- Research, Connexins, Gap junctions (Cell biology) | ||||
| Official Date: | February 2019 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | Warwick Medical School | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Dale, Nicholas ; Wall, Mark J. | ||||
| Sponsors: | Medical Research Council (Great Britain) | ||||
| Format of File: | |||||
| Extent: | 189 pages : illustrations, charts | ||||
| Language: | eng |
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