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

点击翻译按钮获取中文摘要

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.