调控神经突触释放外泌体抑制高糖诱导的小口径工程血管钙化的研究

This project will be focus on the problem of calcification of small-caliber engineering vascular implantation in body with diabetes. From the microenvironment after implantation, our group found when nerve fibers grow into the blood vessels can inhibit calcification. But the mechanism is not yet clear. Exosomes may carry miRNAs by acting neuroendocrine effects on smooth muscle cells and may regulate the phenotypic transformation to inhibit vascular calcification. We would like to play the advantages in the construction of small diameter engineering blood vessels, to study the effect and mechanism of promoting the release of exosomes release by synaptic in diabetic patients: 1. To investigate the effect of exosomes release on the proliferation and calcification of smooth muscle cells induced by high glucose by DENND1A, and to elucidate the molecular mechanism of neurotransmitter release active substance to regulate the phenotype transformation of vascular smooth muscle cells; 2. DENND1A and Netrin-1 were used to construct small-caliber engineering blood vessels with nano-gold microcapsule system. Then, we characterized and tested them in vitro. 3. By constructing DENND1A and netrin-1 composite modified layer by layer self-assembly small diameter engineeried vessels, we study the mechanisms of regulation of vascular smooth muscle function in vivo and of vessel calcification induced by high glucose. The completion of the project will provide a new perspective for the construction of anti-disease vascular grafts.

项目针对血管植入物在糖尿病个体容易钙化的难题，从血管植入后与机体微环境的交互作用入手，在课题组前期发现神经纤维长入工程血管后能够抑制钙化，但机制尚不清楚的基础上，基于神经外泌体可能携带miRNA等通过神经内分泌作用于平滑肌细胞，调控表型转化从而抑制血管钙化。发挥课题组在小口径工程血管体内构建中的优势，深入研究糖尿病下通过促进神经突触释放外泌体抑制工程血管钙化的作用和机制：1）明确通过DENND1A促进神经外泌体释放对高糖诱导的平滑肌细胞异常增殖迁移和钙化等的影响和分子机制；2）通过纳米金微囊系统构建DENND1A与Netrin-1复合修饰的层层自组装小口径工程血管，并进行表征和体外检测；3）DENND1A与Netrin-1复合修饰的层层自组装小口径工程血管移植后在体研究其调控工程血管平滑肌功能，抑制高糖诱导的血管钙化的作用和机制。项目完成将为构建抗疾病的小口径组织工程血管提供新视角。

项目针对血管植入物在糖尿病个体容易钙化的难题，从血管植入后与机体微环境的交互作用入手，在课题组前期发现神经纤维长入工程血管后能够抑制钙化，但机制尚不清楚的基础上，基于神经外泌体可能携带miRNA等通过神经内分泌作用于平滑肌细胞，调控表型转化从而抑制血管钙化。发挥课题组在小口径工程血管体内构建中的优势，深入研究糖尿病下通过促进神经突触释放外泌体抑制工程血管钙化的作用和机制：1、发现神经外泌体能够调控平滑肌细胞表型转化，但是神经外泌体在高糖环境下分泌减少，DENND1A 能够促进高糖下神经外泌体释放。2、构建程序化二级响应系统，通过按需释放设计，构建DENND1A 与 Netrin-1 复合修饰的层层自组装小口径工程血管。实现小口径血管神经长入同时，促进神经外泌体的释放。3、通过长时程观察，发现二级响应修饰的小口径工程血管在高糖下有效抑制内膜增生，从而率先构建了抗内膜增生的小口径组织工程血管。项目的完成为构建抗疾病的小口径组织工程血管提供新视角。