PKCε通路双重调控SDF-1/CXCR4轴介导间充质干细胞归巢与旁分泌治疗DHCA诱导肺损伤研究

CPB postoperative respiratory dysfunction is one of the major causes of morbidity and mortality after cardiac surgery . There is no effective treatment . Stem cell therapy for the CPB lung injury has opened a new way. The less the number of stem cell homing , cell differentiation and survival rate, seriously affecting stem cell transplantation . Now that the SDF-1/CXCR4 axis mediated stem cell homing and PI3K/AKT pathways mediated by Stem cell secreting next stem cell transplant success rate. PKCε is a key link in the CPB organ protection , but it is homing of stem cells and secretory function in the role next to the yet to be verified . We propose the following hypothesis : PKCε signaling pathways regulating SDF-1/CXCR4 axis and dual PI3K/AKT pathway mediated bone marrow mesenchymal stem cell homing and paracrine functions in stem cell transplantation to repair CPB plays an important role in lung injury . This project PKCε as a starting point , to be established bone marrow cell model mesenchymal stem cells and whole animal models , application of molecular biological methods , from the cells and the overall level clarify PKCε signals on stem cell homing and paracrine effects of and possible mechanisms to improve stem cell homing and paracrine mechanisms , the discovery of new targets and more effective interventions to improve the efficacy of stem cell transplantation provides important clues and evidence.

CPB术后呼吸功能障碍是心脏外科术后重要并发症和死亡原因。目前尚无有效治疗方法。干细胞为CPB肺损伤治疗开辟一条新途径。而干细胞归巢数量少、细胞分化和生存率低，严重影响干细胞移植效果。目前认为SDF-1/CXCR4轴介导干细胞归巢和PI3K/AKT途径介导干细胞旁分泌可影响干细胞移植成功率。PKCε在CPB器官保护中处于关键环节，但它在干细胞归巢和旁分泌功能中的作用尚待验证。我们提出以下假说：PKCε信号通路双重调控SDF-1/CXCR4轴与PI3K/AKT途径介导骨髓间充质干细胞归巢与旁分泌功能，在干细胞移植修复CPB肺损伤中起重要作用。本项目以PKCε为切入点，拟建立骨髓间充质干细胞细胞模型和整体动物模型，应用分子生物学方法，从细胞和整体水平阐明PKCε信号对干细胞归巢和旁分泌影响及可能机制，为发现新的干预靶点和更有效的改善干细胞移植疗效提供重要线索和依据。

深低温停循环技术应用于复杂先天性心脏病及大血管疾病的手术治疗中，由其引起的术后呼吸功能障碍是术后重要并发症和死亡原因，目前尚无可靠有效的治疗方法。骨髓间充质干细胞移植治疗相关急性肺损伤为治疗术后呼吸功能障碍提供了新思路，相关信号通路与细胞因子介导了深低温停循环造成的肺损伤过程也影响了骨髓间充质干细胞归巢、分化和生存。本研究发现人骨髓间充质干细胞对抗脂多糖诱导的人肺上皮细胞株A549细胞凋亡和旁分泌作用。通过构建大鼠急性肺损伤模型和骨髓间充质干细胞移植实验，发现骨髓间充质干细胞对急性肺损伤的保护作用与炎症环境下干细胞促进角化细胞生长因子分泌有关。通过建立深低温停循环动物模型发现PI3K/Akt通路对此模型下抗肺部细胞凋亡的影响。为深低温停循环造成的肺损伤与肺保护策略以及骨髓间充质干细胞移植治疗提供了新思路。