糖尿病性动脉粥样硬化是糖尿病常见的大血管并发症，发病机制极其复杂，尚未完全阐明。白细胞分化抗原38(CD38)催化NAADP的合成和降解，NAADP是一种新的诱导溶酶体Ca2+释放的第二信使。本项目利用CD38基因敲除的小鼠冠状动脉平滑肌细胞，建立高糖或者糖基化终末产物诱导细胞损伤的模型，分析CD38/NAADP信号通路调控自噬溶酶体形成和活性，进而影响p62蛋白水平，参与血管平滑肌细胞分化和增殖的机制。同时，利用高脂饲料联合STZ诱导的2型糖尿病性冠状动脉粥样硬化模型，研究CD38/NAADP信号参与小鼠冠状动脉血管平滑肌病理改变和功能损伤。最后，基于CD38/NAADP信号上游调控机制的研究，评估CD38激活剂丙半胱氨酸和其他潜在抗糖尿病药物对糖尿病性冠状动脉粥样硬化的改善作用。本项目揭示糖尿病性冠状动脉功能失调的新机理，对靶向性改善糖尿病血管并发症具有重要理论意义和应用价值。

Diabetic atherosclerosis is a common vascular complication of diabetes. However, the mechanisms underlying the diabetic atherosclerosis are still unclear. CD38 is a multifunctional enzyme responsible for the production and metabolism of nicotinic acid adenine dinucleotide phosphate (NAADP), a new potent Ca2+ mobilizer in lysosomes. Primary mouse coronary arterial myocytes (CAMs) from wild-type and CD38 gene knockout mice are treated with high glucose or advanced glycation end products (AGEs). It is investigated that CD38/NAADP signal pathway regulates autolysosome formation and activity, which is responsible for the degradation of sequestosome1 (SQSTM1/p62), a selective substrate for autophagy. Further study is performed that p62 plays a critical role on the dedifferentiation and proliferation in CAMs. Next, the mouse model of type 2 diabetic atherosclerosis is established with streptozotocin (STZ) and high-fat diet to detect the role of CD38/NAADP signal pathway in pathological process and vascular function. Lastly, based on the upstream mechanisms of CD38/NAADP signal pathway, L-2-oxothiazolidine-4-carboxylic acid (OTC) and other potential anti-diabetic agents are used to test their therapeutic role on coronary atherosclerosis in diabetes. Our study reveals new mechanisms of coronary dysfunction in diabetes, which is of great theatrical and practical significance to improve diabetic vascular complications.