抗凋亡基因BCL-2启动子区i-motif在急性肾损伤中的机理研究及基于该靶点小分子转录调控策略

急性肾损伤（AKI）是一种发病率死亡率极高的危急重症。BCL-2表达量下降导致AKI早期肾小管细胞过分凋亡。BCL-2基因启动子i-Motif是该基因转录的“分子开关”，稳定i-Motif结构后BCL-2表达量增加。前期研究提示AKI肾小管上皮细胞凋亡模型细胞内i-Motif数量较正常组减少，诱导并稳定该结构后细胞存活率提高，因此我们推论BCL-2启动子i-Motif可能是AKI早期肾小管上皮细胞凋亡的新靶点，稳定i-Motif结构后可上调BCL-2基因表达发挥抗凋亡效应。后期将分别从动物模型、临床实验中研究AKI发病过程中肾小管上皮细胞内BCL-2启动子i-Motif结构及其特异性转录因子hnRNP LL的变化。采用特异性配体小分子对AKI细胞及动物凋亡模型进行干预，阐明i-Motif在AKI发病机制中的作用。为基于抗细胞凋亡的AKI发病机制及其治疗提供新的理论及实验依据。

Acute kidney injury (AKI) is a critical illness with extremely high morbidity and mortality. Decrease of BCL-2 expression is an important factor in the progress of AKI, and it is negatively correlated with the excessive apoptosis of renal tubular cells in the early stage of AKI. i-Motif in the P1 region of BCL-2 gene promoter is the "molecular switch" for the transcription of the gene. The expression of BCL-2 increases after the i-Motif structure is stabilized, and the two are positively correlated. Based on this, we speculate that there is also a negative correlation between i-Motif and the excessive apoptosis of renal tubular cells in the early stage of AKI. i-Motif in the P1 region of the BCL-2 promoter may be a new target for early renal tubular epithelial cell apoptosis in AKI. After stabilizing the structure of i-Motif, it up-regulates the expression of BCL-2 gene. In response to this speculation, we have studied the changes in the structure of i-Motif and its specific transcription factors in the P1 region of the BCL-2 promoter in renal tubular epithelial cells during the pathogenesis of AKI from cells, animals, and clinically. Use specific ligand small molecules to intervene in AKI cells and animal apoptosis models to clarify the role of this structure in the pathogenesis of AKI. Provide a new theory and experimental basis for the research on the pathogenesis and treatment of AKI based on anti-apoptosis.