CircRNA_0001428/miR-32-3p/ATF4信号通路下调BCL11A基因介导γ-globin激活而改善重型β-地贫贫血的机制研究

迄今为止，国内外尚无环状RNA（circRNA）与β-地贫相关的报道。本研究前期芯片发现，circRNA_0001428在重型β-地贫中的表达显著下调并与贫血程度呈负相关。细胞实验发现，circRNA_0001428可直接结合miR-32-3p介导转录激活因子4（ATF4）表达上调，而ATF4可直接抑制B细胞淋巴白血病/淋巴瘤11A（BCL11A）基因表达而激活γ-珠蛋白（γ-globin）。据此，我们提出“circRNA_0001428/miR-32-3p/ATF4通路下调BCL11A介导γ-globin激活而改善重型β-地贫贫血”的科学假说。为验证该假说，我们拟采用相应生物学技术分别在分子、细胞及小鼠模型中研究circRNA_0001428对重型β-地贫贫血的治疗作用，并阐明ATF4下调BCL11A介导γ-globin激活的分子机制。本研究将为重型β-地贫贫血的治疗提供新的分子靶点。

So far, there are no reports on the association between circular RNA (circRNA) and β-thalassemia (β-thal) at home and abroad. The preliminary studies of circRNA microarray found that circRNA_0001428 was down-regulated in patients with β-thal major and negatively correlated with the degree of anemia. Cell functional experiments found that circRNA_0001428 directly bound to miR-32-3p-mediated upregulation of.transcriptional activator 4 (activating transcription factor 4),whereas ATF4 directly inhibited B-cell lymphoid leukemia/lymphoma 11A (BCL11A).gene expression to activate γ-globin gene. Accordingly, we proposed a scientific hypothesis that "circRNA_0001428/miR-32-3p/ATF4 pathway down-regulated BCL11A-mediated γ-globin activation to alleviate the anemia of β-thal major". In order to validate this hypothesis, this project intends to use the corresponding biological methods in clinical, molecular, and mouse model to study the therapeutic effects of.circRNA_0001428 on the anemia of β-thal major, and to elucidate the molecular mechanism by which ATF4 directly down-regulated BCL11A-mediated activation of γ-globin gene. This study will provide new molecular targets for the treatment of anemia of β-thal major.