超声联合载SDF-1α微泡促CXCR-4基因修饰的BMSCs归巢修复糖尿病肾病的实验研究

项目名称： 超声联合载SDF-1α微泡促CXCR-4基因修饰的BMSCs归巢修复糖尿病肾病的实验研究

项目编号： No.81501485

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王龚

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： 外周静脉注射骨髓间充质干细胞（BMSCs）能控制糖尿病肾病（DN）的发展，但BMSCs在慢性损伤组织存在移植效率低下的问题，提高BMSCs归巢能力是干细胞治疗的重要策略。SDF-1α/CXCR-4轴是参与干细胞归巢最重要的分子通路，能抑制移植MSCs凋亡、增加存活率和归巢能力。但研究发现DN患者体内SDF-1α水平减低，体外培养的BMSCs特异性受体CXCR-4随着传代次数增加而较少。课题组前期研究使用超声靶向破坏微泡技术（UTMD）联合脂质体提高CXCR-4基因在BMSCs的转染，能增加体外对SDF-1α特异性迁移能力，但其在DN肾脏中靶向归巢效率仍不满意，DN肾脏组织表达SDF-1α不足是其主要原因。本研究拟制备载SDF-1α微泡，通过UTMD技术使SDF-1α在DN大鼠肾脏靶区高表达，同时使用微泡增加的超声生物学效应，使肾靶区微环境改变，以提高CXCR-4基因修饰BMSCs归巢效率。

中文关键词： 超声微泡；骨髓间充质干细胞；归巢；糖尿病肾病；基因修饰

英文摘要： Bone mesenchymal stem cells (BMSCs) transplantation is an effective mean for the treatment of diabetic nephropathy (DN), but the low transplantation efficiency and poor homing capacity are two unsolved problems. SDF-1 alpha /CXCR-4 axis is involved in the most important molecular pathways of stem cell homing, can inhibit MSCs apoptosis and increase the survival rate and homing ability. But the study found that SDF-1 levels were decreased in DN Patients, the specific CXCR-4 receptor was also also decreased with the passage number cultured in vitro. Our previous study increased CXCR-4 gene modification in BMSCs with the application of UTMD technology combined with liposome. The results were shown to increase the migration ability in vitro of SDF-1alpha specific. , but its homing efficiency in the DN kidney is still not satisfied, the poor expression efficiency in DN renal tissues is the main reasons. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted SDF-1-loaded microbubble (MBSDF-1) via covalent conjugation destruction. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MBSDF-1, in order to increase CXCR-4 gene modified BMSC homing efficiency.

英文关键词： ultrasound microbubble;Bone Mesenchymal Stem Cells;homing;diabetic nephropathy;gene modification