Dietary constituents modulate the healing response through the action of amine oxidases

The maintenance of health and wellbeing requires the complex interaction between biological systems and environmental factors. Dysregulation of the processes governing repair of damaged tissue can result in a loss of tissue function, a process that underpins organ failure in many chronic disorders and aging. It is clear that tackling the problems posed by impaired wound healing responses presents a major socio-economic and health challenge.

The repair and replacement of damaged tissue is a multistep process. Firstly clearance of dead/dying cells and scaffolding proteins that provide a framework for cellular growth is facilitated by specialised immune cells in blood that patrol the circulatory system. This is followed by a co-ordinated invasion by fibroblast cells that form a temporary framework to support the growth of replacement tissue. Once the damaged site has been replaced with healthy tissues the temporary scaffold is then degraded through the programmed cell death of the fibroblasts following further interactions with specialised immune cells. The delicate balance of these processes can be affected by factors such as diet, age and even the type of bacteria present in the gut. This can lead to impairment of responses to tissue injury and the rapidity of age-related scarring.

Natural products present in the diet can regulate the function of amine oxidases, a family of proteins that are present in many cells of the body. They are implicated in the development of chronic disorders and the development of tumours. It is thought that an increased level of these proteins leads to the build-up of damaging immune cells and the production of highly rigid cellular scaffolds. This results in excessive scar formation and impaired function, potentially leading to life threatening disorders. Dietary constituents that are used by amine oxidases can be found in diverse foodstuffs such as fish, meat, vegetables, coffee and wine. They can also be produced by bacteria present in the gut and transported to other parts of the body through the circulation. However it is not clear what impact regulation of these proteins by the diet has on the wound healing process. This project will seek to identify specific dietary components that modulate amine oxidase activity. In this context we will also investigate which members of the amine oxidase protein family can promote immune cell recruitment and exacerbate scar formation.

The identification of dietary mediators of amine oxidase activity will have important implications in tailoring the formulation of diets for individuals such as those with chronic disorders. Understanding the function of each amine oxidase in the maintenance of healthy tissue will have far-reaching consequences for both the long-term goal of development and deployment of medical therapeutic interventions.

Tissue homeostasis requires a coordinated programme of inflammation, regeneration and replacement. The maintenance of homeostasis is underpinned by tightly controlled inflammatory and stromal cell responses. Dysregulation of these processes can result in loss of tissue function and integrity, and is a feature of both humans and animals suffering from chronic conditions such as progressive organ failure. There is mounting evidence that dietary factors and the composition of the gut microbiome can affect an individual's response to tissue injury and the rapidity of age-related scarring. Therefore an understanding of the dietary factors that control of inflammation and wound healing responses is critical to the development of strategies to alleviate these conditions.

The amine oxidases are a group of enzymes that deaminate primary amines such as those found in the diet, or those generated as a consequence of metabolism by gut bacteria. Amine oxidases have been implicated in inflammatory and stromal responses to tissue damage through recruitment of distinct immune cell subsets, stromal cell activation and cross-linking of ECM. Whilst it is known that certain dietary amines are substrates for these enzymes their effects on tissue homeostasis are poorly understood. Furthermore the precise roles of individual members of the amine oxidase family in this process have not been fully described.

This project aims to define the substrate specificity of amine oxidases and their impact on i) wound healing mediated by stromal cells and ii) the recruitment of inflammatory cells. This project will also study systemic effects of amine oxidases mediated by circulating forms of the proteins and highly reactive products of the deamination reaction such as advanced glycation end products. It is anticipated that this project will provide novel data linking diet and health through the action of amine oxidase activity, and inform future approaches to improve the healing response.

Dysregulated tissue repair and homeostasis underlies most chronic conditions and age-related disorders. Despite major health and socio-economic implications the cellular and molecular determinants of impaired responses to wound healing are currently limited. The primary goal of this study is to define dietary regulators of amine oxidases that have an impact on tissue homeostasis.

This study will benefit both academic and non-academic groups with impact expected to come from several main streams:
1. Increase in fundamental knowledge of the function of individual amine oxidases and their interactions with biogenic amines will benefit the wider academic community.
2. Understanding the mechanisms by which amine oxidases modulate wound healing responses will be of interest to researchers such as those studying immune cell-stroma interactions in multiple organ systems.
3. Methodological development in the detection of advanced glycation end products (AGE) will be made available for researchers from diverse streams such as clinical science, pharmacology and biomedical science.
4. Translational potential from the identification of key players in tissue homeostasis will benefit the pharmaceutical and drug-development industries, and in the long-term individuals suffering from related disorders.
5. Identification of dietary components that regulate amine oxidase activity will be relevant to nutritionists and food manufacturers.

Who will benefit from this research and how?
1. Academic research groups at local, national and international level working on nutrition, wound healing, immune responses, ageing and reactive intermediates (such as AGE). Research findings will be disseminated via both Open Access publication and presentation at research meetings and congresses.
2. Students/early career researchers. Students will be engaged through lectures/tutorials and laboratory-based sessions provided by the PI as part of the College of Medical and Dental School teaching programme. Clinical and non-clinical students will be exposed to cutting-edge research and novel methodologies, thereby increasing their knowledge of processes fundamental for health and wellbeing.
3. Research staff. Training in research techniques and professional development opportunities will be provided for the technician employed by this project. This will also benefit other members of the group through development of a broad spectrum of generic and project-specific research skills that align with the BBSRC Skills Statement for research training.
4.Drug-development Industry. Determination of specific amine oxidase proteins responsible for disruption of tissue homeostasis will shape the development and use of therapeutic agents for related disorders.
5. Clinical practitioners and patients. The investigation of dietary substrates for amine oxidases and the consequences for tissue homeostasis is of clear interest to the clinical community in terms of medical research and practice.
6. Wider socio-economic impacts. Development of effective therapeutic strategies may ultimately have a significant impact on the health and wellbeing of patients, enhancing quality of life and improving socio-economic status.
7. Methodology development. This project will develop methods to detect AGE in biological samples that will be of enormous benefit to the global research community, thus increasing the competitiveness of UK science.
8. Food manufacturers and distributors. A number of methods have been developed to control the levels of biogenic amines in the manufacture and storage of foods. The interaction between amine oxidases and these compounds, and their effects on health will have direct impact on the monitoring of biogenic amine levels in foodstuffs.
9. Public. The project will support public engagement to promote dialogue with the wider non-academic community, thereby communicating research outcomes and their relevance to society.