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

随着我们年龄的增长，我们身体的系统功能变得越来越差；使健康和活跃的人变得越来越虚弱。据预测，到2050年，英国将有约1900万65岁以上的人。随着老年人数量的增加，越来越有必要制定战略，促进“健康老龄化”，限制老龄化的负面后果。受老龄化影响的一个重要系统是我们的免疫系统，它影响我们抵抗感染和保持耐受性的能力。这是一个特别的问题，在屏障部位，内部身体和外部世界(如肠道和口腔)之间的界面。这些部位的免疫系统必须调节一种微妙的平衡；它必须防止病原体入侵，并能够将这些有害的入侵者与共生/友好的细菌区分开来。这是一个困难的挑战，为了实现这一点，免疫系统被仔细地定制为屏障部位，创建高度专业化的免疫细胞网络，以加强这种平衡，并确保屏障部位的完整性。随着年龄的增长，保持这种平衡变得越来越困难。虽然在肠道中已经评估了年龄驱动的免疫功能的变化，但年龄对口腔屏障存在的免疫网络的影响仍然是最小的探索。这是一个重大的疏忽，因为年龄的增长伴随着口腔屏障完整性的丧失，以及口腔炎症的发生率和严重性的增加。此外，最近的数据表明，口腔炎症是与不健康老龄化相关的大量疾病的风险因素，包括心血管疾病和糖尿病。因此，了解口腔屏障中与年龄相关的变化变得越来越重要。这项资助的目的是确定口腔屏障免疫反应随年龄的功能变化，并确定在一生中教育口腔屏障免疫网络的口腔特有因素。通过采用我与尖端技术一起开发的新技术，这项工作将改变我们对健康一生中口腔屏障免疫动态平衡的组织特异性控制的理解。特别是，这项工作将评估促进口腔屏障免疫失调调节的因素，并破坏随年龄增长的屏障动态平衡。这项研究将在曼彻斯特大学(UOM)、生命科学学院(FLS)和新的曼彻斯特炎症研究合作中心进行。利用人类样本和免费赠送的小鼠模型，该研究计划将询问口腔屏障免疫剪裁的核心机制。这项工作将得到英国国内和全球许多合作者的支持，他们的专业知识将极大地提高开展这项工作的效率，他们的资源将扩大所开展工作的范围。我已经与耶茨教授(在密歇根大学)建立了临床合作关系，他帮助我开发了临床队列，使我能够从不同年龄的健康人的口腔屏障中获取组织样本。作为补充，一位关键的国际合作者是D.Bowish教授(加拿大麦克马斯特大学)，他是一位免疫衰老专家，他将为我提供接触老龄小鼠队列的机会。这项研究计划的其他合作者是各自领域的专家Y Belkaid博士(NIAID，NIH，美国)和W.Muller教授(UM，英国)。这些创新的研究将提升我们对促进口腔屏障完整性的免疫细胞网络的基本理解。确定在衰老过程中发生变化的机制和促进这些变化的因素提供了一扇治疗机会之窗，以加强老年口腔屏障的完整性，限制口腔炎症，从而在生物体的整个生命周期中保护全身健康。

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.