急性心肌梗死（AMI）可引起心肌细胞过度自噬和凋亡，导致心肌细胞数量减少，最终发展为心力衰竭。近年研究提示长链非编码RNA(lncRNAs) 和微小核苷酸(miRNAs)在多种心脏生理病理过程中起关键作用。我们前期研究发现AMI患者外周血样中lncRNAs的表达发生变化，其中CDR1as表达上调，且在小鼠AMI模型心肌组织中亦显著升高。生物信息学预测推测CDR1as可能是通过直接抑制miR-505而发挥作用。本研究拟采用在体实验动物模型、细胞模型，揭示非编码核苷酸对心肌细胞自噬的调控，从整体、细胞及分子水平上探讨CDR1as的损伤作用及机制，明确其促进自噬和凋亡、最终引起心肌细胞死亡的信号通路。本研究的完成将有利于揭示心肌梗死过程中非编码核苷酸的调控，明确CDR1as是一种细胞死亡的正向调控分子，有望成为AMI早期诊断的生物标志物，最终为急性心肌梗死的预防和临床治疗提出新策略。

Acute myocardial infarction (AMI), a serious threat to human health, could cause excessive autophagy and apoptosis of myocardial cells, resulting in reduction of the number of myocardial cells, and eventually developing into heart failure. Recent researches suggested that long-non-coding RNA (lncRNAs) and microRNA (miRNAs) play key roles in the regulation of various physiological and pathological processes. The preliminary work of our study showed that the expression level of one of lncRNAs, CDR1as, was significantly upregulated in the peripheral blood samples from patients with AMI, which was also significantly elevated in myocardial tissues of AMI model mice. Bioinformatics predicted that CDR1as is likely to play a role in the proecess of AMI by inhibiting miR-505 directly. This present study was designed to reveal the regulation of non coding RNA on autophagy in myocardial cells, further to verify the inhibition of CDR1as on miR-505. From the animal model, cellular as well as molecular level, we planed to reveal the damage effect of CDR1as in cardiomyocytes and further unraveled the involved mechanisms. Luciferase and in situ hybridization techniques will be applied to determine the target of CDR1as. Furthermore, our study will focus on the signaling pathways which were involved in the regulation of noncoding RNA on cellular autophagy and apoptosis, ultimately causing cell death. The completion of this study will contribute to reveal the regulation of non coding RNA in myocardial infarction and make it clear that CDR1as is positive regulator of cell death, which is expected to become important biomarkers of AMI. Finally, our study willl put forward a new strategy for the prevention of acute myocardial infarction.

急性心肌梗死（AMI）可引起心肌细胞过度自噬和凋亡，导致心肌细胞数量减少，最终发展为心力衰竭。近年来研究提示长链非编码核苷酸（lncRNAs）和微小核苷酸（microRNAs）在多种心脏生理病理进程中起到关键作用。在本项目的资助下，我们课题组研究发现AMI患者外周血样中lncRNAs的表达发生变化，其中CDR1as表达上调，且在小鼠AMI模型的心肌组织和血液样本中亦显著升高。生物信息学预测CDR1as可能是通过直接抑制miR-183而发挥作用。我们在细胞水平上诱导自噬潮，建立研究模型。我们发现miR-183和其潜在下游靶点UVRAG均受到自噬水平的影响。在细胞中过表达miR-183可以抑制自噬的活性。相反，抑制内源性miR-183可以提高自噬的活性。进一步的研究发现，UVRAG是miR-183的直接靶点，并且是miR-183发挥自噬活性调控功能的关键中介。大量证据表明自噬和凋亡在心肌梗死损伤中并没有相互的依赖性，可能在患者的心脏中共存着凋亡和自噬性死亡。我们给予细胞3-MA（自噬抑制剂）和/或Z-VAD-FMK（凋亡抑制剂）处理后，发现miR-183参与细胞死亡的调控机制包括凋亡和自噬两个途径，而UVRAG在自噬和凋亡过程中起到交叉调控的重要作用。最后，在体水平实验中，我们证实miR-183的拮抗剂antagomiR-183具有促进自噬的作用。这说明miR-183对自噬的抑制作用在体内也存在，并暗示miR-183可以作为临床治疗的干预靶点。