发育不良性椎弓峡部裂是一类由椎弓发育异常引起的脊柱疾病，其发病机制尚不清楚。课题组前期研究发现：①首次于疾病家系中证实SLC26A2基因突变（p.D673V）参与疾病发生，但致病机制亟待阐述；②FGFR3信号通路在SLC26A2敲除软骨细胞中存在异常激活，且SLC26A2敲除小鼠椎体-神经弓软骨结合（NCS）提前骨化。有文献表明NCS异常骨化会导致椎弓发育畸形。据此，我们推测SLC26A2突变可能通过异常激活FGFR3信号通路促使NCS提前骨化，最终导致椎弓发育异常、诱发峡部裂的发生。本项目拟利用多种SLC26A2相关模式动物，明确软骨源性的NCS提前骨化是SLC26A2突变的关键致病环节，阐明SLC26A2突变通过调控FGFR3通路诱发NCS早闭的分子机制，提出并验证潜在的创新药物干预策略。本课题将首次揭示发育不良性椎弓峡部裂的确切发病机制，为治疗药物的研发与转化提供可靠的理论依据。

Dysplastic spondylolysis is a spinal condition caused by developmental defects in the vertebral arch, whose pathogenesis remains unclear. Our team previously found: 1) the SLC26A2 mutation (p.D673V) was confirmed for the first time in an affected family to participate in the onset of the disease but the pathogenic mechanism is unexplored; 2) the FGFR3 signaling pathway was abnormally activated in SLC26A2 knockout chondrocytes, and SLC26A2 knockout mice displayed premature ossification of neurocentral synchondroses (NCS). It was reported that premature ossification of NCS could cause dysplastic vertebral arch. Based on the above-mentioned, we further speculate that the SLC26A2 mutation might promote ossification of NCS by over-activating the FGFR3 signaling pathway, eventually leading to dysplastic vertebral arch and the onset of pars lysis. This project intends to use multiple SLC26A2-related mouse models to verify that premature ossification of NCS is the key pathogenic process of the SLC26A2 mutation, to clarify the molecular mechanism through which the SLC26A2 mutation induces premature closure of NCS by regulating the FGFR3 signaling pathway, and to propose and verify the potential drug intervention strategy. This project will reveal for the first time the exact pathogenesis of dysplastic spondylolysis and provide reliable evidence for the drug development and clinical translation.