严重抑郁症（Major depressive disorder，MDD）预计在2030年将为全球疾病负担第一位，而当前数据显示中国抑郁症患者人数已超9500万人，关联近3亿家庭人口。因此，抑郁相关分子机制研究一直是神经18新利备用网站 领域的热点及难点。脑源性神经营养因子（BDNF）、血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）等生长因子以及抗抑郁药物均可通过促血管新生（Angiogenesis）达到抗抑郁作用[1]，脑卒中等血管疾病也与抑郁关系密切[2, 3]。

曹聪课题组多年来致力于研究G蛋白抑制性α亚单位1和3（Gαi1/3蛋白），并证实Gαi1/3是抑郁新分子靶点。在多个生长因子刺激下，Gαi1/3与受体酪氨酸激酶（RTKs）等受体结合介导下游信号转导（Protein & Cell 2022 [4]，Science Signaling， 2009[5]，Oncogene 2018, 2021[6, 7]，IJBS 2022[8]，Theranostics2018，2021a/b[9-11]等论文）。课题组前期研究发现抑郁患者及抑郁模型小鼠海马区Gαi1/3表达显著下调；而敲减、敲除Gαi1/3后，海马神经元树突数目及单位距离的树突棘的数目均显著减少，小鼠表现典型的抑郁样行为。（PNAS 2018[12]，Highlight by PNAS[13]）。但Gαi1/3蛋白表达调控的分子机制并不明确。

2022年5月27日，18新利体育 曹聪课题组在Science Advances发表了题为“The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo”研究论文，该研究揭示了磷酸烯醇丙酮酸羧激酶1（PCK1）在促Gαi3表达及血管新生中的关键作用。

研究发现在体外培养的人脐静脉内皮细胞、人视网膜毛细血管内皮细胞和人脑微血管内皮细胞中，敲减及敲除PCK1抑制细胞成管、增殖、迁移、浸润及出芽；而过表达PCK1促体外血管新生作用。C57小鼠内皮细胞特异性敲减PCK1后显著抑制P1（出生后第一天）到P5小鼠视网膜血管发育；在成年小鼠中，PCK1敲减导致视网膜血管渗漏和无细胞毛细血管生长，同时降低视网膜神经节细胞的数量。

PCK1是催化糖异生关键限速酶，而机制研究发现PCK1的促血管作用并不依赖于其促糖异生功能。PCK1与转录因子GATA4互作并促GATA4磷酸化；后者通过与Gαi3启动子结合，促Gαi3转录、表达及下游Akt的活化，最终导致血管新生。而敲减、敲除PCK1几乎阻断GATA4磷酸化，下调Gαi3表达及Akt的活化。总之，PCK1通过介导Gαi3表达及Akt活化促血管新生，PCK1是抑郁及血管新生的新靶点。

参考文献

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