ALDH2调节有氧糖酵解在急性肾损伤管球反馈机制中的时空组学研究

脓毒血症AKI危害大缺乏有效治疗，我们近期发现80%重症新冠AKI为线粒体受累的急性肾小管损伤（ATI），通过生信分析和线粒体损伤-AKI模型证实线粒体乙醛脱氢酶2（ALDH2）重塑近端小管（PTC）有氧糖酵解而预防AKI。本研究①首先利用脓毒血症队列观察ALDH2基因突变酶活性降低与AKI发生和预后关系；②在ALDH2-/-、FGFBP1-/- 和管球反馈（TGF）缺失A1AR-/-小鼠中，用显微灌注和体外TGF细胞共培养技术，首次从器官、组织、细胞和分子水平，观察低ALDH2影响TGF三个关键环节降低GFR的机制；③利用原位单细胞测序（Stereo-Seq）探索胎肾发育和AKI损伤修复不同阶段调控TGF的关键分子，如FGFBP1-FGF2-FGFR在PTC和入球动脉的不同效应；④最后尝试用超声微泡-光声成像搭载质粒靶向治疗，为脓毒血症AKI防治提供新思路。

Sepsis-induced acute kidney injury (AKI) is critical and lacks effective treatment. Recently, we observed acute tubule injury (ATI) with mitochondrial disorder in 80% severe COVID-19 AKI patients. Noticed by the bioinformatics data, we firstly confirmed that aldehyde dehydrogenase 2 (ALDH2) plays an important role in aerobic glycolysis regulation in PTC of mitochondrial injury-induced AKI model. Firstly, we will clarify the relationship between the low ALDH2 activity with gene mutation and the morbidity and mortality of AKI in a cohort study of patients with sepsis-induced AKI. Then in wild type, ALDH2, FGFBP1, and A1AR knockout mice, we would use micro-perfusion and in vitro macular densa (MD) co-culture system to clarify the mechanism of ALDH2 effect on three critical points of tubulo-glomerular feedback (TGF), resulting in the decrease of GFR. Thirdly, in the in situ single-cell sequencing (Stereo-Seq) technique, we would explore the molecules of TGF during fetal kidney development and AKI repair in different stages. Finally, we will use photoacoustic imaging and Dye-ALDH2/FGF2-plasmid loaded microbubble to precisely target the PTC and juxtaglomerular apparatus. It is supposed to provide a new idea for the prevention and therapy of sepsis-induced AKI.