TRAIL促早期动脉粥样硬化硬化形成作用靶点及机制的研究

Accumulating evidence indicates that TRAIL has a critical role in modulating vascular biology and disease. Indeed, both clinical and animal studies suggest that TRAIL may have a vascular protective role by suppressing the process of atherosclerosis, although the mechanisms of this anti-atherogenic action are not totally understood. In light of these findings, it is proposed that TRAIL not only serves as a biomarker of cardiovascular disease, whereas TRAIL-based therapies may have beneficial pharmacological effects in treating cardiovascular diseases such as atherosclerosis. During atherogenesis, macrophages migrate into the subendothelial space and internalize chemically modified low-density lipoproteins (LDL), leading to formation of cholesterol-laden foam cells. This process is the central pathophysiological mechanism responsible for the initiation of atherosclerosis. Studies have demonstrated that lipid uptake by macrophages is mediated by various types of scavenger receptors. However, whether TRAIL has any effects on expression of macrophage scavenger receptors and lipid uptake by macrophages has not yet been studied. Based on these observations, we hypothesized that TRAIL might have anti-atherogenic effects by regulating lipid uptake and scavenger receptor expression in macrophages in vitro. Further more, we will try to find the mechanism of it. This is meaningful and beneficial for the study of atherosclerosis.

目前有关TRAIL诱导的凋亡效应在动脉粥样硬化不稳定性斑块形成中的作用机制研究报道甚少。现有的研究TRAIL在调节血管的生理和疾病中所扮演的角色存在争议。这些研究均提示我们TRAIL不仅仅是动脉粥样硬化的生物学标志物，它在动脉粥样硬化的进程中扮演重要的角色，并有可能成为动脉粥样硬化治疗的生物学靶点。有研究表明TRAIL能抑制动脉粥样硬化的进展，既然如此，TRAIL是否能通过影响清道夫受体对巨噬细胞脂质摄取产生影响尚不清楚。基于上述发现，我们提出如下假说：TRAIL的抗动脉粥样硬化作用可能通过调节脂质的摄取及巨噬细胞表面清道夫受体的表达来实现。本课题拟通过体外细胞学研究验证TRAIL是否通过抑制巨噬细胞吞噬脂质减少巨噬细胞转化为泡沫细胞减轻动脉粥样硬化的进展；TRAIL是通过何种清道夫受体发挥作用并探讨其可能的作用机制并进一步体外探讨TRAIL对巨噬细胞及平滑肌细胞凋亡的影响。本研究对明确TRAIL在AS发展过程中的作用具有重要的科学意义，并阐述TRAIL尚未被认识的可能的作用机制，同时可能为临床提供新颖、有效的治疗手段。

目前有关TRAIL诱导的凋亡效应在动脉粥样硬化不稳定性斑块形成中的作用机制研究报道甚少。现有的研究TRAIL在调节血管的生理和疾病中所扮演的角色存在争议。这些研究均提示我们TRAIL不仅仅是动脉粥样硬化的生物学标志物，它在动脉粥样硬化的进程中扮演重要的角色，并有可能成为动脉粥样硬化治疗的生物学靶点。有研究表明TRAIL能抑制动脉粥样硬化的进展，既然如此，TRAIL是否能通过影响清道夫受体对巨噬细胞脂质摄取产生影响尚不清楚。本课题通过研究表明：TRAIL的抗动脉粥样硬化作用可能通过调节脂质的摄取及巨噬细胞表面清道夫受体的表达来实现。然而，结果与我们预想结果恰恰相反，TRAIL促进了动脉粥样硬化的进展。本课题通过体外细胞学研究验证TRAIL促进巨噬细胞吞噬脂质增加了巨噬细胞转化为泡沫细胞促进动脉粥样硬化的进展；TRAIL如何调节清道夫受体发挥作用并探讨了其可能的作用机制，并进一步体外探讨TRAIL对巨噬细胞及平滑肌细胞凋亡的影响。本研究对明确TRAIL在AS发展过程中的作用具有重要的科学意义，并阐述TRAIL尚未被认识的可能的作用机制，同时可能为临床提供新颖、有效的治疗手段。