CD47在糖尿病心肌病中介导炎症反应、细胞凋亡及微循环障碍的机理研究

Diabetes is a global issue, particularly in China. Diabetic cardiomyopathy (DCM) is one of severe complications of diabetes and is a significant cause of the mortality of diabetic patients. Therefore, it is urgent for us to develop new approaches to prevent the development of DCM. In cancer research, we have approved that CD47 plays important role in inducing cell death and suppressing angiogenesis. Meanwhile, our preliminary studies on diabetic complications also showed the increased expression of CD47 as well as its related ligand TSP-1 and receptor SIRP in the heart of diabetic mice; Therefore, we hypothesize that CD47 may play the same role as in tumors, in promoting diabetes-induced cardiac inflammation, cell death and angiogenesis impairment. The present project will test our hypothesis by performing the following studies: (1) To systemically examine the mRNA and protein expressions of CD47, TSP - 1, and SIRP and their associated pathogenic alterations in the heart of type 1 and type 2 diabetic mice; (2) Using CD47- KO, TSP-1-KO, and SIRPα - KO transgenic mice, to define the critical role of CD47, TSP-1 and SIRP in the development of DCM; (3) To investigate the preventive or therapeutic effect of anti-CD47 antibody on the development of DCM in both type 1 and type 2 diabetes mouse model, which may provide a new road for developing effective approach to prevent and/or treat DCM for diabetic patients in the future.

糖尿病心肌病(DCM)增加了糖尿病患者死亡率，所以如何预防DCM凾需解决。在肿瘤研究中我们发现CD47可诱导肿瘤细胞死亡和抑制血管增殖。我们发现糖尿病的心肌CD47及其相关的TSP-1和SIRP也增高。因此，我们假设CD47以及TSP-1和SIRP在糖尿病心肌中可能起着类似肿在瘤中的作用，促进心肌炎症、细胞死亡、新生血管增殖抑制而加速DCM发展。本研究拟系统的观察CD47、TSP-1、SIRP mRNA和蛋白在小鼠1型和2型糖尿病心肌中的动态表达以及相关的病理作用；并应用CD47、TSP-1和SIRP基因敲除小鼠，进一步研究CD47、TSP-1和SIRP在糖尿病心肌中的作用机制。在确定CD47在糖尿病中有加速DCM作用后，继续探讨应用CD47抗体预防和治疗1型和2型糖尿病小鼠DCM可行性，为糖尿病DCM的预防和/或治疗提供新方法、新途径。

脓毒症是感染所致的全身炎症反应综合征，进一步发展可导致感染性休克和多脏器功能不全综合征。是临床危重症主要死亡原因。脓毒症所致的心脏功能不全在脓毒症患者中并不少见，是决定脓毒症预后的主要因素之一，其中脓毒症性心脏功能不全的发生机制尚未完全阐明，涉及多方面原因。我们在WT及CD47KO糖尿病小鼠模型中发现， CD47KO小鼠感染和死亡率更低，心功能更好。这提示我们CD47可能与感染相关。因此我们探究了CD47在脓毒症及脓毒症心肌病中的作用。我们发现，CD47KO的脓毒症小鼠心功能较WT的脓毒症小鼠好，通过对比检测WT小鼠与WT脓毒症小鼠CD47心肌表达的差异，说明脓毒症确实可以上调CD47的表达，且这种上调与炎症因子的表达相关，而上调的 CD47蛋白进一步促进炎症细胞浸润，加重心肌损伤。综合上述结果，研究为探讨CD47在LPS介导的脓毒性心肌病中的作用机制奠定了工作基础。项目共资助发表论文13篇，SCI论文12篇，培养博士研究生2名，硕士研究生3名。项目投入55.000万元，支出47.1414 万元，各项支出基本与预算相符。剩余经费7.8586万元，剩余经费计划用于本项目研究后续支出。