Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase whosedysfunction has been identified in many diseases ranging from cancer
to Down’s syndrome. Previous studies have examined salivary gland
atrophy and observed the submandibular gland’s ability to regenerate
from atrophy, however the mechanism underlying this process is still
unknown. The current study aims to investigate the effects of blocking
mTOR signaling in atrophic salivary glands and blocking mTOR
signalling in submandibular glands regenerating from atrophy.
The first part of the study revealed that inhibition of mTOR delays
ligation-induced atrophy of salivary glands and that furthermore,
mTOR could only be inhibited for shorter periods of 3 days, whereas 5
or 7 days of ligation and rapamycin treatment cause glands to
re-express active mTOR and show considerable signs of atrophy.
The second part of the study aimed to find out the reasoning behind the
reactivation of mTOR following 5 or 7 days, despite the presence of
mTOR inhibitors. It concluded that 2nd generation mTOR inhibitors also
failed to block mTOR activation following 7 days of atrophy. Proteomic
and microarray analysis were performed and gave rise to possible
future enquiries.
This study then exposed the role of mTOR in salivary gland
regeneration following atrophy, revealing that mTORC1, specifically its
substrates, are needed for a full regeneration. Inhibiting mTOR during
periods of atrophy and allowing phosphorylation of mTORC1 substrates
during periods of regeneration, is a treatment method which could be of
importance.
The final part of the study observed samples of atrophic human salivary
glands in order to find evidence of aberrant mTOR activity. It caused
three realisations, firstly that mTOR is one of the driving forces of
atrophic processes as once atrophy is severe, most acinar cells are lost
and mTOR is no longer as active. Secondly, that autophagy coincides
with salivary gland atrophy in humans. And thirdly, that some salivary
gland functions might possibly be intrinsically linked to ageing.
This leads to the suggestion that the future of treating salivary gland
atrophy in humans could lie in using mTOR inhibitors, whether they be
localised treatment in the form of intraductal injection of rapamycin
loaded nanoparticles to get localised targeting whilst reducing whole
body toxicity or in the form of combination therapies that combine
mTOR inhbitiors with the addition of another drug that inhibits
autophagy and counteracts any toxic effects of mTOR inhibition.
| Date of Award | 2016 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Gordon Proctor (Supervisor) & Guy Carpenter (Supervisor) |