TPPP3基因在肥胖发生发展过程中的作用机制研究

Obesity has become a serious threat to human health, increasing the national burden of disease worldwide. Promote microtubule proteinaggregation3 (TPPP3) is a newly discovered microtubule-interacting protein (MAP),which may be the role of microtubule protein affecting cell proliferation.TPPP3-based research group first cloned the gene from the pituitary tissue in 2000 and was named as a international new protein. Its role in obesity is unclear. Our previous studies showed that the inhibition of TPPP3 expression in cervical cancer cells HELA could interfere with mitosis and cell cycle progression and deterred the proliferation and metastasis of cells. Currently, TPPP3 knockout model has been prepared and identified by the DNA and protein levels successfully .Induced by high-fat, TPPP3 knockout mice showed a significant obesity, increased weight, higher blood pressure, higher blood glucose, higher insulin and increased food intake compared with the control group. The project intends to reveal the regulatory mechanisms of TPPP3 in lipid synthesis and insulin function in obesity, and may provide new drug targets for the prevention and treatment of obesity.

肥胖已经成为当前严重威胁人类健康、增加国民负担的全球性疾病。促微管聚集蛋白3（TPPP3）是新近发现的微管相互作用蛋白（MAP），其可通过与微管蛋白作用而影响细胞增殖。TPPP3为本课题组2000年在国际上首次在垂体组织中克隆得到并命名的新蛋白，它在肥胖发生中的作用尚不清楚。我们的前期研究表明，在宫颈癌细胞HELA中抑制TPPP3表达，能干扰细胞有丝分裂和细胞周期的进程从而阻遏细胞的增殖和转移。目前，已制备TPPP3基因剔除模型，经DNA及蛋白水平鉴定模型成功，经高脂诱导，TPPP3基因剔除小鼠较对照组出现明显的肥胖、体重、血压、血糖、胰岛素及摄食增加，本项目拟在前期基础上揭示TPPP3对肥胖发生中脂质合成和胰岛素功能的调控机制，为肥胖的防治提供新的药物靶点。

促微管聚集蛋白（ TPPPs）是可以与微管互相联系，并且能够增加微管汇集，从而维持微管体系稳定的一类蛋白质。课题组首次克隆微管蛋白聚合启动蛋白(TPPP3)，并成功地建立了TPPP3 基因敲除小鼠 (TPPP3-KO)。课题组发现：高脂喂养的TPPP3-KO小鼠可以降低众多指标，包括体重、血脂、血糖、脂肪沉积、血炎症指标、 组织的炎症浸润及Homa指数等。同时，TPPP3-KO小鼠可以抵抗高脂诱导的体内NF-κB 通路的活化从而表现出抗炎的效应，同时肝脏的胰岛素通路也明显活化。在巨噬细胞中抑制TPPP3基因表达可以降低炎症信号通路NF-κB的活化，从而抑制炎症反应，而在巨噬细胞中过表达TPPP3可以促进巨噬细胞中炎症信号通路 NF-κB 的活化，从而发挥促炎效应。在内皮细胞中抑制TPPP3表达可以降低高脂引起的氧化应激损伤、增加抗氧化能力，降低炎症反应，改善内皮细胞功能；而在内皮细胞中过表达TPPP3可以促进氧化应激损伤、降低抗氧化能力，增加炎症反应，损伤内皮细胞功能。同时课题组利用酵母双杂交发现了 TPPP3 的一个相互作用蛋白---RanBP9。TPPP3可能通过Ranbp9调控细胞增殖和促炎作用。TPPP3在代谢性疾病的发病过程中发挥重要作用，可能成为治疗代谢性疾病的一个新的靶点。