Determining the role of Wnt signalling & IGFBP6 in enhanced atherosclerosis risk in periodontal patients: biomarker & therapeutic potential evaluation

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Heart attacks are one of the leading causes of death in the UK and across the world. The most common cause of heart attacks is the blockage of the arteries that supply the heart. These blockages are caused by a disease called atherosclerosis. Atherosclerosis occurs when fat (cholesterol) accumulates in the arteries, resulting in the inflammation, thickening, and hardening of the artery vessel wall. People with periodontal disease - a chronic infection of the gums - are especially likely to develop atherosclerosis. However, many people are unaware that this gum disease puts individuals at a greater risk of having a heart attack. Moreover, the precise link between atherosclerosis and periodontal disease remains a mystery. A greater understanding of the link between these diseases is essential in order to reduce the number of heart attacks. My Fellowship will investigate this little explored connection. I have recently generated novel data that shows a protein known as Insulin-like Growth Factor Binding Protein 6 (IGFBP6) and a signalling pathway called Wnt are significantly altered in monocytes collected from patients with gum disease. In the light of such observations, we believe that these targets (IGFBP6 protein and Wnt signalling) cause important changes in the behaviour of monocytes in patients with gum disease, which subsequently increase the risk of atherosclerosis and the incidence of heart attacks. To investigate this phenomenon, three approaches will be used. The first focuses on the regulation of monocytes behaviour, a type of white blood cell which causes inflammation and drives atherosclerosis, by IGFBP6 and Wnt signalling. I will collect cells from healthy controls and patients with periodontitis, and alter the level of the targets (IGFBP6 protein and Wnt signalling) using various approaches, and then quantify the effect on essential pro-atherosclerotic behaviour traits of monocyte/macrophages in culture. Secondly, I will utilise a well-established model of mouse atherosclerosis to validate my findings with the cultured cells, and evaluate the potential use of these targets as biomarkers or open possibility for treatments. Thirdly, I will use samples from patients with periodontal disease and healthy individuals to validate the biomarker findings from the animal model in human samples, which is essential to illustrate the translational potential to clinical benefit.The longer-term benefit of the research will be to develop new treatments for patients suffering from periodontitis and/or atherosclerosis, thereby preventing the likelihood of heart attacks. The treatments would aim to suppress the effects of monocytes, and retard inflammation and the associated blockages in the arteries. Additionally, we believe that IGFBP6 (or members of the Wnt signalling pathway) could act as a biomarker of disease and could be utilised for monitoring progression of disease and success of treatments. Furthermore, gum disease has been linked with other diseases such as stroke, diabetes and rheumatoid arthritis, so my research will have significant implications beyond atherosclerosis.