ACAT1通过HSPA9调控过氧化物酶体稳态减轻急性肾损伤的作用和机制研究

肾小管上皮细胞能量代谢失调是导致急性肾损伤（AKI）发生发展的关键因素。我们前期研究发现乙酰辅酶A酰基转移酶（ACAT1）丰度与肾损伤进程密切相关，ACAT1与热休克蛋白家族A成员9（HSPA9）相互作用介导的过氧化物酶体稳态参与此过程。基于此，本项目将进一步深入研究肾损伤进展过程中，ACAT1通过调控HSPA9而介导过氧化物酶体稳态，促进细胞能量代谢、保护肾小管上皮细胞的功能与机制。通过细胞实验、小鼠AKI模型和ACAT1转基因鼠模型，结合临床样本分析，首先证明ACAT1在AKI过程中的肾脏保护功能；据此进一步明确ACAT1通过HSPA9调控过氧化物酶体稳态、保护肾功能的分子机制，并阐释ACAT1/HSPA9介导的分子网络；基于分子基础的阐释，评估ACAT1及关键调控节点在临床AKI中的价值。本项目将提出AKI过程中，肾脏代谢稳态改变的新调控机制，为临床AKI监测及治疗提供新视角。

Dysregulation of energy metabolism in renal tubular epithelial cells plays critical roles in mediating the progression of acute kidney injury (AKI). Our preliminary studies showed that the expression level of acetoacetyl-CoA acetyltransferase 1 (ACAT1) was tightly related with the progression of kidney injury, and that the interaction between ACAT1 and heat shock protein family A member 9 (HSPA9)-mediated peroxisomal homeostasis plays an important role in this process. Based on these findings, we will aim to investigate the function and mechanism underlying ACAT1/HSPA9 interaction-mediated maintenance of peroxisomal homeostasis, promotion of energy metabolism and protection of renal tubular epithelial cells against AKI. Firstly, we will investigate the functional action of ACAT1 in protecting kidney against AKI by integral analyses of cell-based experiments, AKI mice models, ACAT1 transgenic mice, as well as clinical samples. Secondly, we will determine ACAT1/HSPA9 interaction-mediated molecular networks in regulating peroxisomal homeostasis and renal protection. Finally, based on the findings in molecular mechanisms, we will assess the clinical values of ACAT1 and its downstream key checkpoints in AKI. This project will endeavor to elucidate a new mechanism in regulating the metabolic alterations during kidney injury, and hold the potential in clinically monitoring and treating AKI.