分子生物钟在机体能量代谢调控中起着至关重要的作用。但是在外周组织中，调控分子生物钟振荡信号的发生机制仍未研究透彻。我们的前期工作发现肝脏中视黄醇结合蛋白4（RBP4）可以与分子生物钟关键转录抑制因子CRY1相互结合，并影响后者的蛋白稳定性。因此，我们有理由猜测RBP4可以通过调控CRY1来影响肝脏生物钟振荡信号的产生。在本项目中，我们将利用RBP4基因敲除小鼠，结合腺病毒介导的sh-RNAi基因沉默或者CRISPR/CAS9基因编辑系统，通过体内、体外实验，探讨RBP4调控CRY1蛋白活性的机制，及其对分子生物钟振荡信号发生的影响，并进一步研究RBP4-CRY1互作在生物钟调控肝脏糖代谢过程中的作用，为理解外周生物钟信号的发生及其调控糖代谢网络的分子机制提供新的理论基础。

Molecular circadian clock regulates the oscillatory expression of many critical genes involved in hepatic glucoase/lipid metabolism. However, the regulation of the oscillatory signaling generation by peripheral circadian clock remains elusive. In our previous study, we found that retinol binding protein (RBP4) is capable of interacting with CRY1, one of the key transcriptional inhibitor in molecular clock machinery, which affects the protein stability of CRY1. Thus, we hypothersize that RBP4 would regulate hepatic clock via CRY1. We will use RBP4 knockout mice and adenovirus-delivered sh-RNAi or CRISPR/CAS9 system to explore the role of RBP4 in regulating circadian clock and RBP4-CRY1 interaction in modulating glucose metabolism in the liver. Our proposed research will shed new lights on understanding the underlying mechamism of circadian clock signaling generation and its function in the regulation of glucose homeostasis.