基于线粒体氧化应激损伤的糖尿病心衰机制研究及其靶向干预的分子成像评价

Diabetes is a common metabolic disease, and heart failure is supposed to be one of the most serious complications of diatetes. Diabetic heart failure emerges as a serious health problem for its poor prognosis and difficult clinical management. To investigate myocardial injury mechanisms and explore target therapy is an urgent task for diabetic heart failure interventions. In view of these dilemmas, we intend to further explore the mechanisms of mitochondrial oxidative stress injury in diabetic cardiomyopathy, and to choice targeted drugs on the basis of blocking and intervention these mechanisms. Ultrasound microbubbles will be synthetized for carrying the targeted drugs (α- lipoic acid). These microbubbles will bind with specific target on cardiac microvessels via antigen-antibody complex system (ICAM-1/CD54), so as to achieve the key aim of drug load, automatic targeting, site release, and targeted intervention. Simultaneously, the mechanism of targeting treatment with antioxidant (α- lipoic acid) will be further expounded and validated its therapeutic effect on the basis of myocardial apoptosis, angiogenesis, myocardial collagen fiber formation and inhibition. With target-specific MMP-2 ( MMP-2-Gd-DOTA) nanoprobe, we are hopeful that the therapeutic process would be dynamically monitored and the treat effects could also be noninvasively assessed in vivo with noninvasive MRI molecular imaging techniques. Most importantly, the research proposal may be potential to establish new strategies and methods for investigating myocardial injury mechanisms, exploring target therapy, monitoring dynamically the therapeutic procedure and assessing noninvasively the target treatment effects in clinical practice of prevention and treatment the diabetic heart failure.

糖尿病是一种常见的代谢性疾病，而心衰是糖尿病最为严重的并发症之一。糖尿病心衰患者预后差，临床处理困难，因此亟需深入研究其心肌损伤机制并积极探索靶向干预措施。有鉴于此，课题组拟深入探索糖尿病心肌病的线粒体氧化应激损伤机制，从而筛选出靶向治疗药物；以纳米生物技术合成载靶向药物（α-硫辛酸）的超声微泡，到达心脏后通过抗原抗体复合系统（ICAM-1/CD54）与心肌微血管上的靶标特异结合，实现药物载荷、定点释放、自动寻靶和靶向干预。同时，以心肌细胞凋亡、微血管生成、心肌胶原纤维的形成和抑制为切入点去阐释靶向抗氧化剂α-硫辛酸的作用机理并验证其治疗效果。构建能够针对MMP-2的靶向特异性成像分子探针，采用无创MRI成像技术从分子水平去动态监测治疗过程和量化评价治疗效果。相关研究成果可望为防治糖尿病心衰研究过程中深入阐释心肌损伤机制、积极探索靶向干预措施及无创动态评价靶向治疗效果提供新思路。

糖尿病心衰患者预后差，临床处理困难，因此亟需深入研究其心肌损伤机制并积极探索靶向干预措施。课题组通过构建糖尿病心肌损伤动物模型，采用商用钆造影剂和/或靶向特异性成像分子探针CHP-SPIO-anti MMP-2进行心脏磁共振扫描，结合血液生化、组织病理学及电镜结果，深入探索糖尿病心肌损伤的线粒体氧化应激损伤机制，证实了糖尿病状态引起氧化和抗氧化系统失衡，通过一系列反应，直接或者间接导致心肌肥厚、纤维化、微循环障碍。进一步使用抗氧化剂α-硫辛酸对实验动物进行治疗，结合靶向特异性成像分子探针CHP-SPIO-anti MMP-2进行分子成像证实了抗氧化治疗能够削弱糖尿病引起的心脏损伤。本课题的实验方法技术实现了部分临床转化，证实了糖尿病早期的心肌损伤，部分成果已经完成发表。总之，研究发现了糖尿病对心脏的早期损伤作用效果，为糖尿病心衰机制研究提供了影像学技术方法，证实了线粒体氧化应激损伤对糖尿病引起的心衰的作用机制，并基于损伤机制提供了可行性的治疗方案，为临床早期干预治疗提供科学依据。