经下丘脑AgRP神经元LEPR介导的瘦素-骨代谢偶联在青少年特发性脊柱侧凸发病机制中的研究

青少年特发性脊柱侧凸（AIS）是最常见的一类脊柱畸形，其高昂的手术费用给社会和家庭造成沉重经济负担。AIS病人存在瘦素生物利用度异常、椎体骨密度降低现象，提示瘦素-骨代谢偶联可能在其发病机制中发挥重要作用。我们在中国汉人中验证了rs2767485为AIS易感位点，且TC基因型的血清LEPR水平呈下降趋势，提示其可能为LEPR基因的功能性多态位点。同时AIS病人椎旁肌NPY受体呈差异表达。此外，我们发现LEPR主要通过中枢途径影响中轴骨密度，但其关键作用靶点和机制尚不明确。本课题将首先通过大样本AIS分析其易感位点、血清学指标、中轴骨密度的相互关系；再通过基因鼠模型研究下丘脑AgRP神经元LEPR在瘦素-骨代谢偶联中的作用和机制；最后明确LEPR对椎旁肌失平衡的作用途径。本课题有望阐明经下丘脑AgRP神经元LEPR介导的瘦素-骨代谢偶联在AIS中的发病机制，为AIS的预防和治疗供新思路。

Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity, and the high cost of its surgical treatment imposes a heavy economic burden on society and families. Abnormal leptin bioavailability and decreased vertebral bone mineral density in AIS patients suggest that leptin-bone metabolism coupling may play an important role in its pathogenesis. In the early stage, we has repeatedly verified that rs2767485 is the susceptible loci for Chinese Han AIS, and the serum LEPR level of genotype TC showed a decreasing trend, suggesting that it may be the functional polymorphism loci of LEPR gene. Meanwhile, the expression of NPY receptors in AIS paravertebral muscle was asymmetry. In addition, we found that LEPR mainly affected the axial bone density through the central pathway, but its key target and mechanism were still unclear. In this study, a large sample of AIS patients would be recruited to explore the correlation among susceptibility loci, serological indicators and clinical characteristics. In addition, the role and mechanism of AgRP neurons LEPR in hypothalamus for leptin-bone metabolism coupling would be investigated with genetically engineered mouse. Finally, the mechanism of LEPR on paravertebral muscle imbalance would also be studied. This study is expected to preliminarily elucidate the pathogenesis of leptin-bone metabolism coupling in AIS mediated by LEPR of AgRP neurons in the hypothalamus, and it would provide new insights for the prevention and treatment of AIS.