内皮祖细胞Sonic hedgehog通路受损在糖尿病合并心肌梗死中的作用及机制研究

Till now, the prevalence of total diabetes and pre-diabetes in our country were up to 92.4 million and 148.2 million, respectively. The major and serious problems in diabetic patients are tissue damage or organs injuries. Among all the diabetic complications, the hazard of diabetes with myocardial infarction is located in the forefront. Compared with non-diabetics, the incidence of myocardial infarction in diabetic patients is higher and the recovery is slower, resulting in higher mortality rates. However, the mechanism is still not fully understood. Our previous results have shown that impaired sonic hedgehog (Shh) pathway contributes to cardiac dysfunction in type 1 diabetic myocardial infarction, but the mechanism is unclear. Diabetic myocardial infarction involves in poor angiogenesis and lower cardiac repair capacity, which results in exacerbated cardiac dysfunction and high mortality. Endothelial progenitor cell (EPC) participates in angiogenesis and tissue repair, but the number and the function of EPC are impaired in diabetes. More evidence reveals that activation of Shh pathway in EPC directly promotes its migration, adhesion and tube formation. Therefore, we hypothesize that the impaired Shh pathway in EPC induces its dysfunction, which eventually results in the lower repair capacity and the consequent cardiac dysfunction of diabetic myocardial infarction. This research focuses on the effect and mechanism of impaired Shh pathway in EPC on the function of EPC, and the effect on the lower cardiac repair and the exacerbated cardiac dysfunction in diabetes with myocardial infarction. We hope that this research will supply more novel experiment data and find new targets, which would explore new strategies for diabetic myocardial infarction in the clinical practice.

糖尿病合并心肌梗死因预后差，死亡率高，其危害程度位居糖尿病并发症前列，且其发病机制仍未完全阐明。Sonic hedgehog（Shh）通路对组织损伤的修复具有重要作用。我们最近的研究结果表明，糖尿病Shh通路受损是糖尿病合并心肌梗死（DMI）心功能障碍加重的重要因素，但其机制不明。DMI涉及血管新生障碍，心肌修复能力降低。内皮祖细胞（EPC）参与血管新生和组织修复，但在糖尿病时其数量和功能都是下降的。研究表明，激活Shh通路可直接促进EPC迁移、粘附和小管形成。因此，我们的研究设想为糖尿病EPC的Shh通路受损引起EPC功能障碍，最终导致DMI修复能力下降，进而心功能障碍加重。本项目探讨糖尿病EPC的Shh通路受损对EPC功能的影响及机制，以及这种影响对DMI修复能力下降、心功能障碍加重的作用。希望通过以上问题的探讨为DMI的临床防治开拓新思路。

项目背景：.糖尿病合并心肌梗死因预后差，死亡率高，其危害程度位居糖尿病并发症前列，且其发病机制仍未完全阐明。Sonic hedgehog（Shh）通路对组织损伤的修复具有重要作用。我们最近的研究结果表明，糖尿病Shh 通路受损是糖尿病合并心肌梗死（DMI）心功能障碍加重的重要因素，但其机制不明。DMI 涉及血管新生障碍，心肌修复能力降低。内皮祖细胞（EPC）参与血管新生和组织修复，但在糖尿病时其数量和功能都是下降的。研究表明，激活Shh 通路可直接促进EPC 迁移、粘附和小管形成。因此，我们的研究设想为糖尿病EPC 的Shh 通路受损引起EPC 功能障碍，最终导致DMI 修复能力下降，进而心功能障碍加重。本项目探讨糖尿病EPC 的Shh 通路受损对EPC 功能的影响及机制，以及这种影响对DMI 修复能力下降、心功能障碍加重的作用。希望通过以上问题的探讨为DMI 的临床防治开拓新思路。..研究内容：.1，研究糖尿病小鼠骨髓EPC 的Shh 通路受损对EPC 功能的影响:.2，研究骨髓EPC 的Shh 通路受损对糖尿病小鼠合并心肌梗死的影响；..重要结果：.1，糖尿病内皮祖细胞Shh通路受损，伴随凋亡增加和功能障碍.2，给予Shh通路激动剂改善功能障碍和凋亡.3，缺氧情况下糖尿病内皮祖细胞Shh通路激活障碍，给予Shh蛋白改善其凋亡.4，Shh-MMP2通路受损导致糖尿病内皮祖细胞功能障碍.5，Shh-Bmi1通路受损导致糖尿病内皮祖细胞缺氧时凋亡增加.6，Shh腺病毒修饰糖尿病内皮祖细胞改善糖尿病心肌梗死细胞凋亡.7，Shh腺病毒修饰糖尿病内皮祖细胞改善糖尿病心肌梗死周边区毛细血管密度、梗死比例、心功能障碍.8，Shh腺病毒修饰糖尿病内皮祖细胞通过分泌外泌体改善缺氧心肌细胞凋亡和促进内皮细胞血管形成..关键数据及其科学意义：.明确骨髓内皮祖细胞Shh 通路受损对糖尿病骨髓内皮祖细胞功能障碍和凋亡增加的作用和机制，以及这种作用对糖尿病合并心肌梗死心肌修复能力下降，心功能障碍加重的影响。通过改善糖尿病内皮祖细胞Shh通路受损，恢复其功能和抗凋亡能力，从而为临床上糖尿病心肌梗死病人自体细胞治疗提供新策略。