Defining the molecular mechanisms underpinning inflammatory regulation of the vasculature

该项目将研究新型抗炎化合物在心血管系统调节中的效用。心血管疾病（CVD）仍然是全球死亡的主要原因，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。先前抑制炎症反应的尝试导致对感染的易感性增加。因此，了解炎症调节的分子机制及其对心血管疾病的影响对于健康和开发更有效的疗法至关重要。具体来说，本研究将研究激活“高度可药用”甲酰基肽受体2（FPR 2）所涉及的分子过程。研究表明，FPR 2在控制从促炎症到促消退信号传导的转换以实现组织愈合方面至关重要，因此已被提议作为开发针对慢性炎症的新型治疗方法的潜在候选者。令人兴奋的是，我们最近的工作发现了新的见解，表明FPR 2的内吞运输对于炎症的解决至关重要。我们已经发现FPR 2运输的破坏增加了细胞凋亡;报告为解决的关键要求。这一发现为理解炎症和治疗方法的发展提供了一个新的分子靶点。最后，FPR 2刺激的结果是配体特异性的，并且可以确定信号传导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知之甚少。本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.