基质筛分效应调节C-反应蛋白血液-组织交换的机制研究

Subtle elevation of circulating C-reactive protein (CRP) predicts risk of multiple diseases, including cardiovascular disease. CRP is also present in early atherosclerotic plaques, where it may contribute to disease progression. However, it remains elusive whether circulating CRP can enter plaques in aorta walls lining by a continuous endothelial barrier, or whether lesion-derived CRP can conversely be transported out of aortas into the circulation. Our preliminary results indicate that circulating CRP can be transcytosed into tissues across continuous endothelial barrier in vitro and in vivo. However, the sieving effect of the basement membrane (BM) matrix that underlies the basolateral surfaces of the endothelial barrier physically hinders the diffusion of CRP transcytosed from the blood, leading to immediate retrograde transcytosis that counteracts its tissue accumulation. Moreover, this mechanism may also contribute lesion-derived CRP into the circulation. This project aims to further delineate the mechanism of CRP transcytosis, demonstrate the general regulation of BM sieving on blood-tissue exchange of proteins and clarify the contribution of lesion-derived CRP to disease progression and elevation of circulating CRP level.

血液中的C-反应蛋白（C-reactive protein, CRP）主要由肝脏分泌，其水平的微小升高预示多种疾病的发生风险，而处于病灶组织中的CRP则可能直接参与疾病的发展过程。我们的前期工作发现，血液中的CRP虽可跨越血管内皮屏障进入组织，但会因内皮屏障下方基膜（basement membrane）的筛分效应（sieving effect）被即刻反向输出，从而阻止了血液CRP在病灶中的积累，暗示病灶中的CRP主要来自原位合成。我们进一步发现，病灶组织原位产生的CRP则可能转运入血液，贡献于与疾病风险相关的血液水平微小升高。本项目将进一步刻画CRP及其激活态构象的跨内皮屏障转运途径，阐明基膜筛分效应调节CRP转运方向偏好性的机制及普适性，澄清病灶局部合成的CRP在血管炎症调节及风险预测中的确切贡献，回答现存重要争议，揭示调节蛋白血液-组织分配平衡的一种通用机制。

本项目围绕C-反应蛋白（C-reactive protein, CRP）在血液-组织间的交换机制展开深入研究，构建了研究蛋白质血液-组织交换的离体和在体模型，解析了CRP跨越内皮屏障进行双向转运的途径，揭示了内皮屏障下方基底膜（basement membrane, BM）的筛分效应是使CRP进入组织后发生即刻反向转运、避免其过度积累的重要基础，很可能代表一种调节蛋白血液-组织分配平衡的通用机制。本项目进一步提出了不同来源CRP在疾病进程中的贡献差异及动物模型设计的新考量，并基于此阐明了CRP在急性组织损伤中的功能、保护机制及靶向干预潜力，回答了领域中长期存在的重要争议。