Defining the molecular mechanisms underpinning inflammatory regulation of the vasculature

本项目将研究新型抗炎化合物在心血管系统调节中的应用。心血管疾病(CVD)仍然是全球最主要的死亡原因，在苏格兰排名第一，现在人们普遍认为慢性炎症是疾病进展的主要驱动因素。以前抑制炎症反应的尝试导致了感染易感性的增加。因此，了解炎症调控的分子机制及其对心血管疾病的贡献对于人们的健康和开发更有效的治疗方法至关重要。具体地说，本研究将研究通过激活高度可药物的甲酰肽受体2(FPR2)而参与的分子过程。研究表明，FPR2在控制从促炎信号到促分辨信号的转换以实现组织愈合方面是必不可少的，因此，已被建议作为开发针对慢性炎症的新疗法的潜在候选者。令人兴奋的是，我们最近的工作发现了新的见解，表明FPR2的内吞运输对于炎症的消退至关重要。我们已经发现，中断FPR2的运输增加了细胞的凋亡；据报道，这是解决问题的关键要求。这一发现为理解炎症和治疗的发展提供了一个新的分子靶点。最后，FPR2刺激的结果是特定于配体的，可以决定信号传递是有益的还是有害的。然而，定义这些相反的生理结果的分子机制却知之甚少。这项研究将阐明这些过程。

This project will investigate the utility of novel anti-inflammatory compounds in the regulation of the cardiovascular system. Cardiovascular disease (CVD) remains the leading cause of death worldwide, number 1 in Scotland and it is now widely accepted that chronic inflammation is a major driver of disease progression. Previous attempts to inhibit the inflammatory response have resulted in an increased susceptibility to infection. Hence, understanding the molecular mechanisms underlying inflammation regulation and its contribution to CVD is therefore critical to well-being and for the development of more effective therapies.Specifically, this study will investigate the molecular processes engaged by activation of the 'highly druggable' formyl peptide receptor 2 (FPR2). Research has shown FPR2 is essential in controlling the switch from pro-inflammation to pro-resolution signalling to enable tissue healing and, as such, has been proposed as a potential candidate for the development of novel therapeutics targeting chronic inflammation. Excitingly, our recent work has uncovered new insight, indicating endocytic trafficking of FPR2 is critical for the resolution of inflammation. We have discovered disruption of FPR2 trafficking increased cellular apoptosis; reported as a key requirement for resolution. This finding provides a novel molecular target for understanding inflammation and the development of therapeutics. Finally, the consequences of FPR2 stimulation is ligand-specific and can determine whether signalling is beneficial or detrimental. However, the molecular mechanisms defining these opposing physiological outcomes are poorly understood. This study will elucidate these processes.