Abstract
There is a global epidemic of type 2 diabetes (T2D), commonly associated with chronic non-healingwounds, almost inevitably complicated with infection. Despite this, experimental research into
wound healing largely focuses on sterile wounds in otherwise healthy individuals. Therefore,
there exists a need to study more complex wound environments. Nevertheless, when using evolu-
tionarily distant organisms such as the fruit fly Drosophila, considering the human relevance
using genetic epidemiological tools is essential to maximise translation. Here, Drosophila was
utilised to model T2D by rearing flies on a high sugar diet (HSD) for 1 (acute HSD) or many
(chronic HSD) generations. In parallel, a mechanical wounding system was developed to allow
modelling of locally infected wounds. Using these approaches, diabetic and infected wound envi-
ronments could be studied in Drosophila using comparative proteomics and confocal microscopy.
Flies reared on an acute HSD recapitulated the published T2D phenotypes and the molecular
profile of acute HSD wounds were inflammatory, as in human diabetic wounds. Surprisingly, the
chronic HSD resulted in a partial rescue of acute HSD phenotypes at all developmental stages, in
both wounded and unwounded tissue. Infected wounds produced an exaggerated version of the
normal wound response, including more widespread cytoprotective (e.g. Nrf2) activation with
increased antimicrobial peptide production and melanisation pathway activation. In addition, a
novel cross-disciplinary, computational genetic epidemiology pipeline was developed to identify
novel gene-trait associations. Here, the pipeline aimed to identify SNPs associated with altered
expression of candidate human genes that were also linked to human phenotypes, in order to
explore the functional relevance of genes of interest.
Overall, we report a Drosophila model of the complex wound environments, diabetes and
infection whilst in parallel, utilising novel genetic epidemiology tools to assess the human
relevance of discovered genes.
| Date of Award | 1 Oct 2024 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Helen M A Weavers (Supervisor), Beck J Richardson (Supervisor) & Nicholas John Timpson (Supervisor) |