Mini-酪氨酰t-RNA合成酶纳米粒在恒河猴急性心肌缺血模型中的血管生成效应研究

In recent years, the prevalence rate and mortality of coronary heart disease(CHD) in the worldwide has been increased year by year, already become the main cause of death in cardiovascular and cerebrovascular disease. Although treatment for coronary heart disease has rapidly been developed, but there is still a considerable number of late coronary heart disease patient, the existing treatment could not take lasting effect. The treatment for such patients need to be actively seeking a new way. This research which has been in our preliminary experiments already confirmed that mini-TyrRS could promote angiogenesis, its acute ischemia angiogenesis effect should been undertaken further research. At the same time, as a result of rhesus monkey in physiology, pathology and genetic aspects is larger than the mouse and other commonly used experimental animal, also been more close to human. It could not only be used as a new model of acute myocardial ischemia and also has a unique advantage for its mechanism, but more important, it could be used for the preclinical evaluation and improve the success rate of clinical trials. In addition, there is evidence which nanoparticles can be used as as macromolecular protein carrier, could reach the target and has slow-release effect, also could be used as an ideal protein carrier system to conduct in-depth research, and the study of angiogenic factor of protein nanoparticles could be applied feasibility and practical treatment effect for the development of coronary heart disease, except that, also very useful and important to generate a new therapeutic approach for CHD.

近年来冠心病的患病率和病死率在全世界范围内呈逐年上升趋势，已经成为心脑血管疾病中主要的死因。虽然冠心病的治疗手段迅猛发展，但是仍有相当数量的晚期冠心病病人，现有的治疗方法难以产生持久的效果，对这类病人的治疗需要积极寻找新的方法。本课题是在课题组前期实验已经证实mini-TyrRS可以促进血管生成的基础上，对其在急性缺血状态下的血管生成效应进行更加深入、细致的研究。同时，由于恒河猴在生理、病理及遗传等各方面都比大小鼠等常用实验动物更接近人类，新模型对急性心肌缺血的机理研究具有独特优势, 更重要的是，它能够用于新药临床前评估，提高临床试验成功率。此外，已有证据显示纳米粒可作为作为大分子的蛋白质的载体，并且可以达到靶向、缓释的效果，可作为一种理想的蛋白因子的载体系统进行深入的研究，而研究促血管生成蛋白因子纳米粒的应用可行性和实际的治疗效果对于开发用于冠心病促血管生成治疗的新途径具有重要的意义。

项目背景 .近年来冠心病的患病率和病死率在全世界范围内呈逐年上升趋势，已经成为心脑血管疾病中主要的死因。虽然冠心病的治疗手段迅猛发展，但是仍有相当数量的晚期冠心病病人，现有的治疗方法难以产生持久的效果，对这类病人的治疗需要积极寻找新的方法。本课题是在课题组前期实验已经证实mini-TyrRS可以促进血管生成的基础上，对其在急性缺血状态下的血管生成效应进行更加深入、细致的研究。同时，由于恒河猴在生理、病理及遗传等各方面都比大小鼠等常用实验动物更接近人类，新模型对急性心肌缺血的机理研究具有独特优势, 更重要的是，它能够用于新药临床前评估，提高临床试验成功率。此外，已有证据显示纳米粒可作为作为大分子的蛋白质的载体，并且可以达到靶向、缓释的效果，可作为一种理想的蛋白因子的载体系统进行深入的研究，而研究促血管生成蛋白因子纳米粒的应用可行性和实际的治疗效果对于开发用于冠心病促血管生成治疗的新途径具有重要的意义。..主要研究内容 .1.mini-TyrRS纳米粒的制备及药剂学性能评价：选用mini-TyrRS为基本的制备药物，以聚乳酸及聚乙醇酸的共聚物为制备纳米粒的载体材料，采用乳化聚合法制备出mini-TyrRS纳米粒，并对纳米粒的药剂学性质，如：粒径、载药量、包封率、载药纳米粒的稳定性、及在体外药物的释放规律进行评价；研究纳米粒在恒河猴正常心肌细胞内的吸收情况和分布，观察对纳米粒进行表面修饰后对粘附与吸收的影响。..2.mini-TyrRS纳米粒在恒河猴急性心肌缺血模型中的促血管生成作用：以结扎左冠状动脉前降支的方法制作恒河猴急性心肌缺血模型，采用局部多点注射给药的方法将mini-TyrRS纳米粒导入缺血区心肌细胞内，对纳米粒在缺血区心肌内的分布进行观察，并对mini-TyrRS纳米粒治疗后心肌梗死面积、微血管形成及心肌细胞增殖的测量。..重要结果.注射mini-TyrRS纳米粒后，与实验对照组相比，可以明显减少心肌梗死面积，增加心肌微血管形成及存活心肌数量，明显改善心脏收缩功能。..关键数据及其科学意义.本课题从构建恒河猴急性心肌缺血模型入手，研究mini-TyrRS纳米粒在心肌梗死后的促血管生成效应，为将mini-TyrRS纳米粒作为新的方法来治疗缺血性心脏病，同时mini-TyrRS纳米粒的制备可以为后续相关课题及研究的开展提供新的技术方法。