牦牛是我国青藏高原主要畜种，高原极端环境下，免疫炎症导致瘤胃上皮发育不良是造成牦牛生长迟缓的重要原因。免疫炎症可诱导组织细胞能量生成由三羧酸循环转向无氧呼吸的代谢重编程，阻碍能量生成和组织发育。人和鼠研究表明苹果酸酶ME1是细胞能量代谢重编程关键调控酶，免疫炎症启动分子补体C3细胞内激活可调控细胞能量生成代谢。申请人前期发现生长迟缓牦牛瘤胃上皮细胞能量代谢重编程，ME1基因下调，补体C3基因上调，但补体C3激活能否调控ME1影响瘤胃上皮能量代谢重编程及其机理不清楚。项目假设生长迟缓牦牛瘤胃上皮细胞补体C3较正常牦牛大量激活，激活产物作用于受体C3aR及下游信号通路，调控ME1影响细胞能量代谢重编程。项目拟比较生长迟缓与正常牦牛原代培养瘤胃上皮细胞C3激活对免疫刺激的差异响应，揭示受体C3aR下游对补体C3激活的应答信号网络，阐明补体C3对生长迟缓牦牛瘤胃上皮细胞能量代谢重编程的影响机理。

Yak is the major livestock in the Qinghai Tibet Plateau of China. Under the extreme plateau environment, immune inflammation induced the rumen maldevelopment is the important reason for the growth retardation of yaks. Immune inflammation reduces the tissue cellular energy biosynthesis by changed the energy biosynthesis from tricarboxylic acid cycle to anaerobic respiration, which is called energy metabolism reprogramming, and inhibits the tissue development. Studies on the human and mouse showed that malic enzyme (ME1) is the key regulatory enzymes for energy metabolism reprogramming, and intracellular activation of complement 3 (C3), a key promoter of immune inflammation, regulated the cellular energy biosynthesis metabolism. My previous study showed that ruminal epithelium of growth retarded yaks had energy metabolism reprogramming, lower ME1 gene expression and higher C3 gene expression. However, the mechanisms of intracellular C3 activation regulating ME1 to affect energy metabolism reprogramming in the rumen epithelial cell is unclear. This project hypothesizes that C3 is higher activated in the rumen epithelial cell of growth retarded yaks than that of normal yaks, and the activated product acts on the receptor C3aR and its downstream signal pathway, to regulate ME1 and affect the energy metabolism reprogramming. This project plan to compare the different responses of intracellular C3 activation to the immunostimulation in primary rumen epithelial cells between growth retarded and normal yaks, reveal the signal network in the downstream of receptor C3aR response to the C3 activation, and illuminate the mechanism of intracellular C3 activation regulated energy metabolism reprogramming in the ruminal epithelium of growth retarded yaks.