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

确定 Wnt 信号传导的作用

基本信息

批准号：
MR/V002007/1
负责人：
金额：
$ 35.65万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV002007%2F1
关键词：
Determining role Wnt signalling IGFBP6

项目摘要

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.

心脏病发作是英国乃至全世界的主要死亡原因之一。心脏病发作最常见的原因是供应心脏的动脉阻塞。这些堵塞是由一种叫做动脉粥样硬化的疾病引起的。当脂肪（胆固醇）在动脉中积聚，导致动脉血管壁炎症、增厚和硬化时，就会发生动脉粥样硬化。患有牙周病（牙龈的一种慢性感染）的人特别容易发展成动脉粥样硬化。然而，很多人都不知道这种牙龈疾病会增加患心脏病的风险。此外，动脉粥样硬化和牙周病之间的确切联系仍然是一个谜。为了减少心脏病发作的次数，更好地了解这些疾病之间的联系是必不可少的。我的团队会调查这个小小的联系。我最近生成的新数据显示，从牙龈疾病患者收集的单核细胞中，一种名为胰岛素样生长因子结合蛋白6 （IGFBP6）的蛋白质和一种名为Wnt的信号通路发生了显著改变。根据这些观察结果，我们认为这些靶点（IGFBP6蛋白和Wnt信号传导）引起牙龈疾病患者单核细胞行为的重要变化，从而增加动脉粥样硬化和心脏病发作的风险。为了研究这一现象，将使用三种方法。第一个重点关注单核细胞行为的调节，单核细胞是一种白细胞，通过IGFBP6和Wnt信号传导引起炎症并驱动动脉粥样硬化。我将收集健康对照和牙周炎患者的细胞，并使用各种方法改变靶标（IGFBP6蛋白和Wnt信号）的水平，然后量化培养中单核细胞/巨噬细胞对基本促动脉粥样硬化行为特征的影响。其次，我将利用一个成熟的小鼠动脉粥样硬化模型，用培养的细胞验证我的发现，并评估这些靶点作为生物标志物的潜在用途或开放治疗的可能性。第三，我将使用来自牙周病患者和健康个体的样本来验证人类样本中动物模型的生物标志物发现，这对于说明转化为临床益处的潜力至关重要。这项研究的长期益处将是为患有牙周炎和/或动脉粥样硬化的患者开发新的治疗方法，从而预防心脏病发作的可能性。治疗的目的是抑制单核细胞的影响，延缓炎症和相关的动脉阻塞。此外，我们相信IGFBP6（或Wnt信号通路的成员）可以作为疾病的生物标志物，并可用于监测疾病的进展和治疗的成功。此外，牙龈疾病与中风、糖尿病和类风湿关节炎等其他疾病有关，因此我的研究将具有除动脉粥样硬化之外的重要意义。