反转昼夜节律上调PER3抑制 NOTCH 通路促进人脂肪细胞分化的机制研究

Obesity is a major disease that seriously affects human health ,the rotation of the circadian rhythm leads to obesity. PER3 (Period Circadian Regulator 3, PER3) is an important member of circadian clock genes regulation loop. PER3 has not been reported in the mechanism study of obesity induced by circadian rhythm rotation. In recent years, PER3 was found to negatively regulate the differentiation of adipocyte in mice, however, we found that the PER3 mRNA expression of obese nurses abdominal subcutaneous adipose tissue with circadian rhythm rotation was significantly higher than normal circadian rhythm of obesity, and PER3 positive regulation of hADSCs differentiation, the human PER3 protein sequence is different from that of the mice, the expression of PER3 mRNA was significantly up-regulated during the induction of hADSCs differentiation,we speculated that PER3 may negatively regulate MIB1 through down-regulation of NOTCH pathway to promote hADSCs differentiation. To prove the above hypothesis, this project intends to use a number of molecular and cell biology techniques, from animal cells, clinical, and other aspects of the circadian rhythm rotation up-regulation of PER3 by down-regulation of MIB1 inhibits NOTCH pathway to promote adipocyte differentiation mechanism, which can provide a theoretical and experimental basis for the prevention and treatment of obesity and its related diseases.

肥胖是严重危害人类健康的重大疾病，反转昼夜节律导致肥胖发生。PER3(Period Circadian Regulator 3,PER3)是昼夜节律时钟基因调控环路重要的成员之一，PER3在反转昼夜节律导致的肥胖机制研究中并无报道。近年来，PER3发现参与负调控小鼠脂肪细胞分化，然而我们发现，反转昼夜节律较正常昼夜节律肥胖人群腹部皮下脂肪组织PER3 mRNA表达显著上调，且人PER3正调控脂肪细胞分化，而人PER3蛋白序列与小鼠差异较大，hADSCs诱导分化过程中PER3 mRNA表达显著上调，我们推测人PER3可能通过负调控MIB1下调NOTCH通路促进hADSCs分化。为证实上述假说，本项目拟利用多项分子、细胞生物学技术，从细胞、动物、临床等不同层面探讨反转昼夜节律上调PER3通过下调MIB1抑制NOTCH通路促进脂肪细胞的分化的机制，为肥胖及相关疾病的预防与治疗提供理论和实验依据。

肥胖是严重危害人类健康的重大疾病，反转昼夜节律导致肥胖发生。PER3(Period Circadian Regulator 3,PER3)是昼夜节律时钟基因调控环路重要的成员之一，PER3在反转昼夜节律导致的肥胖机制研究中并无报道。我们前期的研究发现，反转昼夜节律较正常昼夜节律肥胖人群腹部皮下脂肪组织PER3 mRNA表达显著上调，且人PER3正调控脂肪细胞分化，但机制并不明确。为了研究PER3调控脂肪细胞分化的分子机制，我们首先从体外实验验证了人PER3能够调控人脂肪来源干细胞（hADSCs）的PPARγ的表达，但通过Co-IP实验发现，人PER3并不能直接结合PPARγ，因此，我们通过RNA-seq发现，人PER3负调控Notch1通路，而Notch1通路为经典的负调控脂肪细胞通路，为了寻找人PER3如何调控Notch1通路，我们利用Co-IP + mass spectrometry (MS)发现人PER3通过结合HSP90AA1后，HSP90AA1结合Notch1的启动子，从而调控Notch1通路的表达，此外，体内实验表明，过表达人PRE3显著促进脂肪细胞的生成。我们从细胞、动物、临床等不同层面探讨反转昼夜节律上调PER3通过HSP90AA1抑制NOTCH通路促进脂肪细胞的分化的机制，为肥胖及相关疾病的预防与治疗提供理论和实验依据。

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