慢性炎症与能量代谢紊乱是糖尿病心肌病（DCM）的两种重要病理过程，两者相互影响和调控。研究表明代谢性疾病中AMPK功能失调引起的能量代谢紊乱与Toll样受体4（TLR4）密切相关，但其中的分子机制尚不清晰。MD2是TLR4识别病原配体调节天然免疫的关键辅助蛋白。我们前期研究发现口服MD2特异性抑制剂L6H21阻抑炎症反应，显著缓解1型糖尿病小鼠心肌病且伴随心肌AMPK的激活，提示MD2可能通过炎症或非炎症通路调控AMPK介导DCM的发生发展。本项目拟利用基因编辑、转录组分析和细胞生物学技术，在细胞层面探索MD2调控AMPK活性的上下游分子机制，阐明L6H21的药理作用；在动物水平利用MD2-/-基因敲除小鼠和基于腺相关病毒的心肌特异性启动子驱动沉默技术进行验证。通过本项目的研究有望发现DCM中天然免疫系统对能量代谢的调控新机制，为DCM的临床治疗提供理论依据与候选新药。

Hyperglycemia induced chronic inflammation and energy metabolic disorder, mutual interaction and regulation of each other, take a pivotal role in the pathological process of diabetic cardiomyopathy (DCM). Although it was found that metabolic disorder caused by AMPK dysfunction is closely associated with MD2/TLR4, the underlying mechanism is still unclear. Myeloid differentiation protein 2 (MD2), an accessory protein of Toll-like receptor 4 (TLR4), is key in recognizing the pathogenic ligand to regulate innate immunity system. Our previous study indicated that oral administration of MD2 specific inhibitor L6H21 significantly alleviates myocardial injury by suppressing inflammation in type 1 diabetic mice, accompanied by activation of AMPK. So, we hypothesize that MD2 mediates the development of DCM by regulating AMPK activity through inflammatory dependent or independent pathway. In this project, we will employ gene editing technique, transcriptome analysis and molecular biological methods to explore both upstream and downstream molecular mechanisms of AMPK that regulated by MD2, and pharmacological effects of L6H21 in vitro. MD2-/- knockout mice and adeno-associated virus based tissue specific knockdown methods were used to make confirm in vivo. Through the present study, we will demonstrate a novel mechanism link innate immune system to energy metabolism in metabolic diseases. It will also provide a crucial experimental evidence and a candidate drug for treatment of DCM.