Oral Barrier Immuno-Surviellance; alterations across the life-course

As we age, the systems of our bodies become less well able to function; rendering fit and active people increasingly infirm. It has been predicted that by 2050 there will be ~19 million people in the UK over 65 years of age. With enhanced numbers of elderly people, there becomes an increasing need to develop strategies to promote "healthy ageing", limiting the negative consequences of ageing.

One important system affected by ageing, is our immune system, influencing our ability to both fight infection and maintain tolerance. This is a particular problem at barrier sites, interfaces between the internal body and the external world (such as the gut and oral cavity). The immune system at these sites has to mediate a delicate balance; it must protect against pathogen entry and also be able to distinguish these bad invaders from commensal/friendly bacteria. This is a difficult challenge and to achieve this the immune system is carefully tailored to barrier sites creating highly specialized networks of immune cells that enforce this balance and ensure the integrity of barrier sites. Maintaining this balance becomes increasingly difficult with advancing age.

Although age-driven changes in immune function have been assessed in the gut, the influence of age on the immune network present at the oral barrier remains minimally explored. This is a significant oversight given that advancing age is accompanied by loss of oral barrier integrity and an increased incidence and severity of oral inflammation. Moreover, recent data has shown that oral inflammation is a risk factor for a plethora of disorders associated with unhealthy aging, including cardiovascular disease and diabetes. As such it becomes increasingly important to understand the age-associated changes occurring at the oral barrier.

The objectives of this grant are to determine the functional changes to oral barrier immune responses with age and to define the oral-specific factors that educate the oral barrier immune network across a life-time. By employing novel techniques that I have developed alongside cutting edge-technology, this work will transform our understanding of tissue-specific control of immune homeostasis at the oral barrier throughout a healthy life-time. In particular this work will assess the factors that promote immune dys-regulation at the oral barrier and undermine barrier homeostasis with age.

This research will be undertaken at the University of Manchester (UoM), in the Faculty of Life Sciences (FLS) and the new Manchester Collaborative Centre for Inflammation Research. Employing human samples and complimentary mouse models, this research programme will interrogate the core mechanisms underlying immune tailoring at the oral barrier. This work will be supported by a number of collaborators, both within the UK and globally, whose expertise will greatly enhance the efficiency with which this work is undertaken and whose resources will increase the scope of the work undertaken. I have established a clinical collaboration with Prof. J. Yates (at the UoM), who has helped me to develop clinical cohorts allowing me to obtain tissue samples from the oral barrier of healthy people of different ages. Complimentary to this, a key international collaborator is Prof. D. Bowdish (McMaster University, Canada), an expert in immunological ageing, who will provide me with access to aged-mouse cohorts. Additional collaborators in this research programme are experts in their fields Dr. Y Belkaid (NIAID, NIH, USA) and Prof. W. Muller (UoM, UK).

These innovative studies will elevate our fundamental understanding of the immune cell network promoting oral barrier integrity. Identifying mechanisms that change during ageing and the factors that promote these changes presents a window of therapeutic opportunity to reinforce the integrity of an aged oral barrier, limit oral inflammation and therefore safeguard systemic health, throughout the life-span of an organism.

Ageing affects immune function and alters immune homeostasis at barrier sites. This is particularly important at the oral barrier, where loss of barrier integrity with age is associated with an increased incidence and severity of oral inflammation. Recent data has increasingly shown that oral inflammation is a risk factor for a plethora of systemic inflammatory conditions associated with unhealthy ageing. Despite this, the immuno-surveillance network policing the oral barrier and how this network evolves with age to preserve barrier integrity remains minimally understood.

This application aims to address this gap in knowledge by functionally understanding the unique immunological network present at the oral barrier. The studies outlined will:
(1) Functionally define the changes to the oral barrier immunological network with age. By employing both human samples and mouse models, I will determine, on a systems level, the age-dependent changes to the oral barrier immuno-surveillance network.
2) Delineate the impact of commensal microflora on the development of the oral barrier immunological network, specifically assessing the role of commensal-derived signals in establishing the oral barrier T cell network.
3) Define the mechanisms promoting age-dependent changes in the oral barrier immuno-surveillance network. By employing targeted and genome-wide approaches, I will outline the factors promoting age-associated changes at the oral barrier.

This research program will transform our understanding of tissue-specific control of immune homeostasis at the oral barrier throughout a healthy life-time. Understanding the mechanisms behind immune specialization at the oral barrier will outline possible therapeutic opportunities to intervene to support oral barrier homeostasis, and therefore safeguard systemic health, throughout the life-span of an organism.

Academia; These are the primary beneficiaries of my research, which will be disseminated to this group by the publication of papers and reviews, by giving talks and by presenting posters. As with all good research, the data generated in this proposal will be assimilated by scientists and will then form a foundation upon which future work can be based. This research also builds upon collaborations with clinicians and therefore promotes cross-disciplinary interactions between scientists and clinicians. This will allow both groups to acquire new skill sets and approach their research in new ways. Myself, and my staff, will development new experimental skill-sets whilst undertaking this work, broadening our technical skills and scientific knowledge supporting us as we apply for additional grant funding and new positions within academia and/or industry.
Timescale: Interactions with these beneficiaries will occur throughout the fellowship.

General Public; The UoM engages in science out-reach programmes to disseminate research findings to the general public. This public engagement will be reinforced by the use of social media platforms such as Twitter and by posting news on my webpages. Through these mechanisms, both myself and lab members, will engage the general public. By achieving this, members of the general public will be able to: (1) find out about my research; (2) learn about science careers; (3) understand the principals of scientific research; (4) learn about the immune system; (5) gain an understanding of good oral health; (6) understand what healthy ageing is, and its importance in an ageing society.
Timescale: Interactions with these beneficiaries will occur throughout the fellowship. In addition, annual participation in UoM public outreach programmes will also occur.

Biomedical Industry; My findings will be of interest to the biomedical industry by providing a deeper understanding of how the immune system operates at the oral mucosal barrier. At the UoM I am an affiliate of the Manchester Collaborative Centre for Inflammation Research (MCCIR), a joint venture between the UoM, AstraZeneca and GlaxoSmithKline. I will meet yearly with representatives from industry, and myself and lab members will present at monthly MCCIR-industry seminars.
Timescale: Interactions with these beneficiaries will occur throughout the fellowship in the form of talks, presentations and industry site visits.

Dentists, Dental Organizations and Dental Charities; Performing the research laid out in this proposal will provide insight into mechanisms of immune homeostasis at the oral barrier. Dental practitioners, organisations and charities will benefit from this research by gaining a better understanding of the complex immunological network operating at this barrier. Collectively, they will be engaged through social media platforms and through publication of primary papers, by giving talks and by the targeted use of press releases.
Timescale: Interactions with these beneficiaries will be enhanced by my interactions with Prof. Yates bringing myself and my lab, into continued contact with dental practitioners. Interactions will this group at large will also be increased around the time that I publish papers.

Organisations promoting healthy aging; Ageing promotes loss of oral barrier integrity and increases in oral barrier inflammation. As inflammation at the oral barrier is a risk factor for a plethora of diseases associated with un-healthy ageing, my work will be of interest to those promoting healthy aging. My work will provide basic mechanistic insight into oral barrier homeostasis and outline possible therapeutic opportunities to intervene to reinforce oral barrier homeostasis, and therefore safeguard systemic health, throughout the life-span of an organism.
Timescale: Interactions with these beneficiaries will occur around the time that I publish papers.