PFN1基因c.318_321delTGAC突变导致破骨细胞功能增强的分子机制研究

PFN1基因编码蛋白质肌动蛋白1（Profilin1）。Profilin1是关键的肌动蛋白结合蛋白，在体内广泛表达。我们于2021年在国际上首先报告了PFN1基因杂合突变导致畸形性骨炎伴巨细胞瘤（JBMR，2021），其中c.318_321delTGAC移码突变被意大利学者证实亦可导致畸形性骨炎伴骨肉瘤，证实该位点为热点突变。畸形性骨炎以破骨细胞功能活跃、骨吸收显著增加为特征表现，导致骨膨胀、畸形和骨折等。但作为热点突变的c.318_321delTGAC为何导致破骨细胞功能上调目前尚未阐明。本项目拟利用已建立的PFN1基因c.318_321delTGCC点突变小鼠模型，从分子、细胞和整体水平阐明PFN1基因突变导致破骨细胞功能上调的机制。本项目研究结果有望使PFN1成为新的骨吸收临床标志物，而且对于抑制骨吸收药物的研发具有重要意义。

The PFN1 gene encodes the protein Profilin1.Profilin1 is a key actin binding protein and is widely expressed in vivo. In 2021, we first reported the heterozygous mutation of PFN1 gene leading to Paget's disease of bone (PDB) with giant cell tumor, among which the c.318_321delTGAC mutation was confirmed by Italian scholars to also lead to PDB with osteosarcoma, which confirmed that this mutation was a hot spot mutation. PDB is is characterized by the active function of osteoclasts and increased bone resorption, leading to bone swelling, deformity and fracture. However, the mechanism of the hot spot mutation c.318_321delTGAC leading to the upregulation of osteoclast function has not been clarified yet. This study intends to clarify the mechanism of the osteoclast function upregulation caused by PFN1 gene mutation, at molecular, cellular and whole level, using the established mouse model of PFN1 gene c.318_321delTGCC mutation. The results of this study are expected to make PFN1 a new clinical marker of bone resorption, and it is of great significance for the development of drugs to inhibit bone resorption.