脂质激酶分子 Pip5k1γ 在老年小鼠椎间盘退变中的功能及分子机制研究

椎间盘退行性病变（Degenerative disc disease，DDD）是世界范围内的主要公共健康问题之一，但其分子机制尚不明确。在本研究中，我们发现，在老龄小鼠和人类 DDD 患者的髓核（nucleus pulposus, NP）细胞中， Pip5k1γ（Phosphatidylinositol -4-phosphate 5 -kinases γ）的蛋白表达水平显著下调。条件性敲除髓核细胞中的 Pip5k1γ 会导致老年小鼠出现严重的 DDD 样表型，但对成年小鼠无影响。尤其重要的是，Pip5k1γ 的缺失会减弱二甲双胍对小鼠腰椎失稳（Lumbar spine instability，LSI）诱发的椎间盘病变的改善作用。在新陈代谢水平上，Pip5k1γ 的缺失会减弱 NP 细胞的合成代谢，但不会促进其分解代谢。在细胞水平上，Pip5k1γ 可抑制NP 细胞的细胞衰老，而 Pip5k1γ 的缺失在很大程度上降低了 NP 组织中细胞的活力。此外，Pip5k1γ 还能通过促进 NP 细胞中 CaMKII 的磷酸化来激活 Ampk 信号。总之，我们首次发现了 Pip5k1γ 在促进 NP 细胞新陈代谢和维持椎间盘稳态中的作用，并为治疗 DDD 提供了一个潜在的分子靶点。

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