Newton001: Salivary gland development and regeneration

One of the factors that significantly impinges on the quality of life among elderly people is a decrease in salivary flow (hyposalivation) and a dry mouth (xerostomia). The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Xerostomia leads to problems with speech, taste digestion, mastication and swallowing, and a high incidence of dental caries and candida. There is no cure but chewing gum and artificial saliva are used to relieve the symptoms in many cases. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the mechanisms that drive xerostomia so that new therapies can be found.

Xerostomia can be caused by a number of different factors. Certain medicines cause xerostomia as a side effect, while xerostomia is also a central feature of the auto-immune disease Sjögren Syndrome, which affects up to 3-4% of older adults. Xerostomia is also a feature of some genetic disorders that affect the salivary glands, such as LADD syndrome and ALSG, and is frequently a side effect of head and neck radiotherapy. We aim to study xerostomia using various mouse models of gland dysfunction and regeneration.

This application aims to combine knowledge of salivary gland development with knowledge of salivary gland stem cells from mouse and translate these findings into humans. This is possible through combining research from basic scientists in the UK and clinical researchers in Brazil, with the ultimate goal of creating innovative methods to treat xerostomia.

The partnership activities proposed involve two young Brazilian research academics from Dr. Lourenço's group carrying out basic science research activities within the laboratories of Dr. Tucker and Dr. Miletich for 8 months. The proposal builds up on the success of a PhD student exchange carried out between the three groups in 2013-14. The two Brazilian research academics will use a mouse animal model to address fundamental questions related to 1) mechanisms involved in the embryonic development of salivary glands and 2) the use of adult salivary gland endogenous stem/multipotent cells to regenerate salivary gland function. On the return of the two research academics to Brazil, data generated in a mouse model in the UK will be validated in human normal and pathological tissues.
The project aims to start with a visit of the proposed partners to the Gordon conference on Salivary and exocrine glands, which is scheduled for February 2015 in Galveston, USA. The meeting will present an excellent opportunity for the lab members to meet internationally renowned experts in the field and shape future collaborations and publications. The meeting will be followed by the visit of the two Brazilian research academics to work in the labs of Dr Tucker and Dr Miletich.
The research project in Dr Tucker's group will focus on the analysis of salivary gland dysfunction using a mouse model of two congenital disorders associated with salivary gland aplasia and hypoplasia, Lacrimo-auriculo-dento-digital (LADD) syndrome and Aplasia of Salivary and Lacrimal glands (ASLG). This will involve analysis of a conditional Fgf10 mutant.
The research project in Dr. Miletich's group will focus on the identification in adult salivary glands of epithelial stem/progenitor cells that will form the basis of a salivary gland cell-based stem cell therapy. This project will focus on Lgr5 positive cells in the glands and take advantage of a duct ligation model.

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