CREG在缺血性心肌损伤/心衰能量重构中的作用及机制研究

心肌细胞能量代谢异常，胰岛素抵抗为心肌梗死后心脏重构的可能机制之一。因此寻找心肌细胞糖代谢调控的关键因子可能对心梗后心衰及心脏重构的治疗产生重大影响。CREG基因表达产物可对心血管系统发挥稳态调节作用，我们在国自然青年基金的支持下，利用CREG肝脏特异性敲除/高表达技术首次发现CREG基因可通过直接结合并调控关键因子的磷酸化水平对肝脏糖、脂肪代谢紊乱发挥稳态调节作用，提示CREG可能通过调控能量代谢通路发挥其抗梗死后心脏重构的作用。作为前一课题的延续，本研究拟利用心脏特异性CREG敲除及转基因高表达技术明确CREG在心脏能量代谢通路中的作用，进而利用棕榈酸诱导的心肌细胞胰岛素抵抗模型，探讨CREG是否通过筛选到的潜在靶点c-Cb1发挥作用，最后在小鼠在体模型中，研究CREG是否可以成为调控心肌细胞能量代谢稳态的关键分子。本研究将为阐述心肌细胞胰岛素抵抗机制提供新的依据。

The mechanism of myocardial injury and heart failure induced by coronary heart disease is usually related to abnormal energy metabolism in myocardium. Energy metabolism of myocardium includes fatty acid metabolism and glucose metabolism. These two kinds of metabolism regulate each other in different pathological states. Disorder of fatty acid metabolism and glucose metabolism occurred in early stage of ischemic injury，which may accelerate the progression of heart failure. Thus to find out the key factor may improve the therapy of heart failure. CREG is key gene regulating cardiovascular homeostasis. Under the support of NSFC, present applicant first found that CREG may keep homeostasis for glucose and lipid metabolism by loss and gain function of CREG, which suggested that CREG may be a key gene regulating energy metabolism. Whether CREG improve ischemic myocardial injury and cardiac function by regulating energy metabolism is still unclear. The present study aimed to build myocardial injury and heart failure animal model. Role of CREG in energy metabolism will be studied by conditional knockout and transgene of CREG. Next, abnormal energy metabolism cell model induced by palmitic acid will be used to confirm whether CREG work via potential factor c-Cb1. Finally, effect of CREG regulating cardiac energy metabolism homeostasis will be studied in vivo. The present study will provide new evidence for disorder of fatty acid and glucose metabolism after ischemic myocardial injury and heart failure.