miR-29c调控胰岛素样生长因子1在深低温停循环后的肠道损伤内源性保护机制的研究

Intestinal complications after deep hypothermia circulatory arrest (DHCA) are difficult to diagnose and life-threatening. The key problem of early diagnosis and intervention is to fully recognize the intestinal injury and repair mechanism after DHCA. The microRNA expression pattern of intestinal tissue of rats underwent DHCA showed significantly decrease of miR-29c. The results of microRNA targets prediction indicated that insulin growth factor 1(IGF-1) might be the target gene of miR-29c. IGF-1 negatively regulates the apoptotic process and promotes intestinal restoration. We hypothesized a new endogenous protective mechanism that "the miR-29c is down regulated and increases IGF-1 expression, to alleviate intestinal injury and promote restoration during DHCA ". We will verify the regulating effect of miR-29c to IGF-1, and the protection to intestine and barrier function in vivo and in vitro. In consideration of the stability of microRNA, the miR-29c may be a potential biomarker of intestinal injury after DHCA. We will launch a clinical trial to investigate the relationship between plasma miR-29c and intestinal complications. Eventually we will achieve to provide theoretical basis and new ideas for prevention, diagnosis and therapy of intestinal injury after DHCA .

深低温停循环（DHCA）后肠道并发症发生隐匿，一旦发现难以逆转。充分认识DHCA对肠道的损伤及肠道自身修复机制，从而早期诊断、早期干预是防治肠道并发症的核心。前期DHCA后大鼠肠道组织芯片结果显示miR-29c显著下调，靶基因预测结果提示：胰岛素样生长因子1（IGF-1）很可能是miR-29c的调控靶点，而IGF-1可抑制细胞凋亡, 并促进修复。课题组提出"在DHCA引起炎症和缺血再灌注损伤时，肠道下调miR-29c以提高IGF-1表达，减轻损伤，促进修复"这一全新内源性保护机制假说。在细胞和动物水平验证miR-29c对IGF-1的靶控关系，和miR-29c调节IGF-1对肠道的内源性保护机制。从临床角度研究DHCA患者血浆内miR-29c与肠道并发症的相关性，探讨miR-29c作为潜在生物标记物的可能性。最终为DHCA后肠道损伤的预防、诊断和早期保护性干预提供理论基础与全新思路。

深低温停循环（DHCA）后肠道并发症发生隐匿，一旦发现难以逆转。肠道屏障是阻隔肠道内容物与肠道固有层的屏障，避免发生二者发生相互作用，影响肠道正常功能。充分认识DHCA对肠道的损伤及肠道自身修复机制，从而早期诊断、早期干预是防治肠道并发症的核心。临床上，低温是一种常用的器官保护方式，如，心肺复苏、心血管与器官移植手术等。细胞作为对低温的反馈是其整体蛋白质合成水平下降，但CIRBP却表达升高，其是一种低温诱导的保护蛋白。我们发现DHCA期间会诱导CIRBP产生，产生器官保护作用。建立DHCA大鼠模型，我们发现DHCA期间肠道组织CIRBP表达升高。构建CIRBP敲除大鼠与DHCA模型，发现DHCA期间CIRBP维持肠道屏障功能。进一步分析发现，DHCA期间CIRBP维持肠道屏障相关蛋白表达稳定与结构功能正常。DHCA期间，磷酸肌酸/肌酸系统发挥着重要作用，为肠道屏障稳定提供着能量物质。敲除CIRBP后，DHCA期间磷酸肌酸/肌酸系统功能受到抑制，无法维持肠道屏障稳定，导致肠道功能障碍。当过表达CIRBP时，可以提高停循环温度，避免降温带来的不利影响。因此，总的来说，DHCA期间CIRBP在肠道屏障稳定过程中发挥着重要作用，并且其可以转化成为临床干预靶点。