血管钙化新机制-GDF15介导的单核/巨噬细胞破骨样转分化调节机制研究

Vascular calcification is frequent in the general population, in diabetic patients, in hypertensive patients, and in patients with chronic kidney disease and is associated with a high risk of adverse cardiovascular events. In recent years, there is an increasing evidence now suggests that vascular calcification is an organized, regulated process with many similarities to osteogenesis. In physiological conditions, the osteoblastic-like differentiation and osteoclastic-like differentiation is in balance. In the pathological conditions，an imbalance between the two processes in favour of the osteoblastic-like phenotype could promote vascular calcification. Our previous studies suggested AGEs inhibited monocyte cell osteoclastic-like differentiation by upregulating GDF15 expression. In the present study, in vitro and in vivo, osteoclast-like cell function and specific osteoclast markers are examined after treatment with rearrangement GDF15 and GDF15 blockage. To determine the mechanism by which GDF15 induces such response, we will sight to determine the intracellular pathways activiated including apoptosis, GDF15 receptor expression, and signal transduction. The results will provide exciting opportunities for prevention and therapy of vascular calcification.

血管钙化是动脉粥样硬化、高血压、糖尿病和慢性肾病等疾病共同病理基础，与许多临床事件密切相关。近年来的研究发现，血管钙化是一个细胞介导、类似骨重构的主动调节过程，正常状态下，血管内成骨成份和破骨成份处于平衡状态，防止血管钙化，病理状态下这种平衡被打破。我们前期工作观察到AGEs通过提高GDF15表达抑制单核细胞破骨样转化，本项目拟在在体和离体水平，观察内源性GDF15及其受体的表达；以破骨细胞活性和表面标志为指标，观察GDF15干预对单核细胞破骨样转化表型转变和功能的影响；以细胞凋亡和GDF15受体途径为检测指标，探讨GDF15抑制单核细胞破骨样转化的可能分子机制；以GDF15作用的主要信号转导通路为切入点，探讨血管钙化的细胞内信号转导机制，以期探寻血管钙化发病的新机制和防治策略。