Role of mTOR in salivary gland atrophy and regeneration

• Main Author: Bozorgi, Sophie Shaghayegh
• Other Authors: Proctor, Gordon Burgess ; Carpenter, Guy Howard
• Published: King's College London (University of London) 2016
• Subjects: 615.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700757

The mammalian target of rapamycin (mTOR) is a protein kinase whose dysfunction 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.