抗菌肽LEAP-2通过Ghrelin调控巨噬细胞极化参与肥胖性心肌损伤的分子机制

肥胖可引起心脏结构和功能异常，导致心肌损伤和心力衰竭。我们研究发现在肥胖性心肌损伤患者和小鼠血清中抗菌肽2（LEAP-2）水平升高而Ghrelin水平降低及巨噬细胞M1/M2转型，Ghrelin可调控巨噬细胞相关炎症因子参与心脏保护。据此，我们认为LEAP-2和Ghrelin可能为调控巨噬细胞M1/M2转型的重要信号分子并参与肥胖性心肌损伤。本项目拟研究：1）LEAP-2非竞争抑制Ghrelin的分子机制；2）LEAP-2通过Ghrelin调控巨噬细胞M1/M2转型的分子机制；3）通过LEAP-2-Ghrelin对巨噬细胞M1/M2转型进而保护肥胖性心肌损伤的转化研究。拟通过LEAP-2干预、利用基因敲除小鼠、巨噬细胞和心肌细胞共培养等方式，采用多种分子生物学方法，研究LEAP-2通过Ghrelin调控巨噬细胞极化参与肥胖性心肌损伤的分子机制，为寻找肥胖性心肌损伤的治疗靶点提供科学依据。

Obesity may cause changes in heart structure and function, even leading to myocardial injury and heart failure. We found that the serum level of antimicrobial peptide 2 (LEAP-2) was increased while the level of Ghrelin was decreased and macrophages transformed between M1 and M2 in obese myocardial injury patients and mice. We had reported that Ghrelin protects the heart through regulating macrophage associated inflammatory factors. Therefore, we suggest that LEAP-2 and Ghrelin may be the key molecules involved in macrophage polarization and obesity-induced myocardial injury. The purpose of this project is to explore: 1. The molecular mechanism of LEAP-2 non-competitive inhibiting Ghrelin. 2. The molecular mechanism of LEAP-2 and Ghrelin regulating macrophage transformation between M1 and M2. 3. The mechanism of macrophage transformation between M1 and M2 by intervening of LEAP-2-Ghrelin. So, LEAP-2 intervention, gene knockout mice, co-culture of macrophages and cardiomyocytes will be used, which would explore the molecular mechanism of LEAP-2 and Ghrelin regulating macrophage polarization in obese myocardial injury and provide a scientific basis for finding therapeutic target of obese myocardial injury.