Newton001: Salivary gland development and regeneration
Lead Research Organisation:
King's College London
Department Name: Craniofacial Dev Orthodon and Microbiol
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
N/A
Publications
Teshima TH
(2016)
Apoptosis in Early Salivary Gland Duct Morphogenesis and Lumen Formation.
in Journal of dental research
Teshima TH
(2016)
Apoptosis-associated protein expression in human salivary gland morphogenesis.
in Archives of oral biology
Gaete M
(2022)
Salivary Gland Development in Culture.
in Methods in molecular biology (Clifton, N.J.)
Title | Hidden disabilities artwork |
Description | 3D models of hidden anatomical structures and overlays of patients and their affected structures |
Type Of Art | Artwork |
Year Produced | 2018 |
Impact | Change in attitude of researchers and clinicians documented in blog post regarding exhibition. |
Description | Salivary glands are essential for the maintenance of oral health by providing lubrication and antimicrobial protection to the mucosal and tooth surfaces. Saliva is modified and delivered to the oral cavity by a complex multifunctional ductal system. During development, these ducts form as solid tubes, which undergo cavitation to create lumens. In this grant we followed the process of lumen formation, focusing on the role of programmed cell death, known as apoptosis. We mapped the timing of apoptosis and showed that in the absence of cell death lumens fail to form. This data is important for our understanding of how ductal systems are formed in the embryo, and for our ability to recreate bioengineered ductal systems to repair gland damage. The grant was an important training experience for two junior researchers from Brazil who worked in molecular biology labs in London. They were able to work with cutting edge molecular tools and imaging facilities, helping them to bring back their new expertise to Brazil. One of the Brazilian researchers was subsequently funded by FAPSEP to continue the research into developing glands and has now established an independent Clinical Academic position. |
Exploitation Route | The findings have been taken forward by a number of research groups and is now the main research topic for one of the Brazilian researchers. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Salivary gland development and regeneration: analysis of FGF10 conditional knockout transgenic mice in timed and tissue specific control |
Amount | R$ 80,000 (BRL) |
Funding ID | 15/02824-6 |
Organisation | São Paulo Research Foundation (FAPESP) |
Sector | Public |
Country | Brazil |
Start | 05/2015 |
End | 02/2016 |
Description | Understanding the role of sympathetic innervation during mouse salivary gland development |
Amount | R$ 100,000 (BRL) |
Funding ID | 17/11207-6 |
Organisation | São Paulo Research Foundation (FAPESP) |
Sector | Public |
Country | Brazil |
Start | 07/2017 |
End | 07/2018 |
Description | Collaboration with Artist |
Organisation | King's College London |
Department | Cultural Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The team were involved in a project working with an Artist to understand patients' thoughts on "hidden disabilities". We focused on the salivary glands (xerostoma) and on the ear (hearing loss), talking to patients and using 3D models to explain disorders. The resulting art work was featured at an exhibition at Somerset house, at Bush house and at the Life Sciences Museum at Guy's Hospital, and the process was documented as part of a multi-part blog on Polyphony website for Medical Humanities. |
Collaborator Contribution | The cultural institute funded the cost of 3D printing, display costs and the time of the artist. |
Impact | 4 part blog on Medical HUmanities website https://thepolyphony.org/2018/11/19/a-dry-and-silent-world-notes-on-a-collaboration-part-1-a-little-like-stepping-off-a-precipicw Exhibitions at Somerset house, Life science museum and Bush house (Art in dentistry programme) |
Start Year | 2018 |
Description | Collaboration with Brazilian researcher |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | As a direct result of this award, the Tucker lab has continued to work with and support the career of Dr Tathyane Teshima, resulting in her current position at UCL as an NIHR Academic Clinical Lecturer. The research time for this post will be carried out at KCL, while the clinical time will be carried out at UCL. |
Collaborator Contribution | The visiting researcher on this award, has remained in close contact with the group and we have continued to publish together. |
Impact | Further research papers: Dual Sympathetic Input into Developing Salivary Glands. Teshima THN, Tucker AS, Lourenço SV. J Dent Res. 2019 Sep;98(10):1122-1130. doi: 10.1177/0022034519865222. Epub 2019 Jul 29. PMID: 31356755 FGF10 is an essential regulator of tracheal submucosal gland morphogenesis. May AJ, Teshima THN, Noble A, Tucker AS. Dev Biol. 2019 Jul 15;451(2):158-166. doi: 10.1016/j.ydbio.2019.03.017. Epub 2019 Apr 6. PMID: 30965042 Mapping the distribution of stem/progenitor cells across the mouse middle ear during homeostasis and inflammation. Tucker AS, Dyer CJ, Fons Romero JM, Teshima THN, Fuchs JC, Thompson H. Development. 2018 Jan 11;145(1). pii: dev154393. doi: 10.1242/dev.154393. PMID: 29217752 Multiple Cranial Organ Defects after Conditionally Knocking Out Fgf10 in the Neural Crest. Teshima TH, Lourenco SV, Tucker AS. Front Physiol. 2016 Oct 25;7:488. eCollection 2016. PMID: 27826253 |
Start Year | 2016 |
Description | Art Science collaboration |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Work with an artist and with patients to create artwork to convey the feeling of loss of sensation. The focus was patients with hearing loss and patients with dry mouth (xerostomia leading to taste problems). Series of workshops, blogs and artwork displayed at three venues around London. |
Year(s) Of Engagement Activity | 2018,2019 |
URL | https://www.kcl.ac.uk/cultural/-/projects/hidden-disabilities |
Description | New Scientist Live: event at Excel centre London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Speaking to members of the public about "Apoptosis" and how cell death can shape our bodies, with demonstration of tissue samples viewed through a microscope |
Year(s) Of Engagement Activity | 2016 |
URL | https://live.newscientist.com/ |
Description | Royal Institution Lates: evening of public engagament |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We hosted a stand investigating the role of programmed cell death in development, using models and tissue to explain how organs such as teeth , salivary glands, limbs, are shaped by cell death. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.rigb.org/whats-on/events-2015/july/lates-life-and-death |
Description | School visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Dr Miletich attended Stillness School with a variety of animal skulls from the Life Sciences Museum in King's. A workshop was carried out discussing feeding behaviours with school children aged 7-8. The workshop was very successful with a lot of questions asked both by children and teachers and the school asked me to come back next year. |
Year(s) Of Engagement Activity | 2015 |