维持干细胞能量代谢稳态构建抗高糖损伤的工程血管

This project is aimed at the extensive vascular disease of diabetes and no available alternative TEVB , based on cellular energy homeostasis of stem cell and monocytes conversion plays an important role for constructing a TEBV. We previously found that adenosine can promote endothelial progenitor cells homing to the engineering vessel and can significantly increase the patency rate of TEBV ,based on the advantage in constructing TEBV in vivo and in vitro, further revealing the mechanism of adenosine kinase for the homeostasis of endothelial progenitor cell energy metabolism and monocytes conversion in diabetes mellitus, and constructing a TEBV of resisting to high glucose injury. 1)researching the characteristics and mechanism for the homeostasis of endothelial progenitor cell energy metabolism of adenosine kinase in high glucose environment; 2)When endogenous adenosine released into the extra cellular, researching on the effects and the mechanism of regulation of monocytes conversion; 3) Preparing of photocrosslinked anticoagulant materials, the adenosine kinase siRNA slow releasing nano particles and the specific antibody of CD34 composite are applied to surface engineering vascular modifications, researching on the construction of engineered blood vessel which can resist high glucose injury and intimal hyperplasia. The completion of the project will provide a new method for constructing blood vessel implant anti -disease injury.

本项目针对糖尿病血管病变广泛且无可用的替代血管现状，基于干细胞能量代谢稳态维持及单核细胞表型转化在构建抗高糖损伤的工程血管中的重要作用。在本课题组前期发现腺苷促进内皮祖细胞归巢于工程血管显著提高工程血管通畅率重要进展基础上，发挥课题组在工程血管体内外构建中的优势，进一步揭示调控腺苷激酶在干细胞能量代谢稳态维持及促进单核细胞表型转化中的作用及机制，进而构建抗高糖损伤的工程血管：1）腺苷激酶调控对内皮祖细胞能量代谢稳态维持进而抗高糖损伤的作用及机制；2）腺苷激酶促进内源性腺苷释放到胞外，调控单核细胞表型转换的作用及其机制；3）制备光交联抗凝材料，将腺苷激酶siRNA纳米缓释颗粒和CD34特异性抗体复合应用于工程血管表面修饰，构建抗高糖损伤及内膜增生的工程血管。项目的完成将为构建抗疾病损伤的血管植入物提供新的方法。

影响小口径人工血管通畅率的主要因素为急性血栓和内膜增生导致的管腔狭窄。内皮层对防止血栓形成和维持血管的稳态有着重要作用，促进内皮化是人工血管维持通畅的关键。糖尿病血管病变是糖尿病并发症中普遍存在并且严重的并发症之一。其血管移植术后，病理状态下参与血管移植物内皮化的细胞的功能会减弱，血管移植物更容易发生病变以及堵塞。针对以上问题，本课题围绕调控腺苷激酶在干细胞能量代谢稳态维持及促进单核细胞表型转化中的作用及机制及抗高糖损伤的工程血管构建进行了研究，明确了调控腺苷激酶诱导内源性腺苷增加在高糖环境下维持干细胞的能量稳态、调控细胞自噬与能量代谢平衡以及优化内皮祖细胞归巢微环境的分子机制。明确了糖尿病状态下，腺苷激酶siRNA 对单核细胞表型转换的作用及其机制，以及单核细胞核型转换对于工程血管化的作用及分子机制。进一步应用适配子嵌合体构建具有良好的抗高糖损伤和抑制内膜增生的层层自组装组织工程血管，为疾病下工程血管构建提供了新的策略。发表SCI论文4篇，申请国家发明专利5项，授权2项，培养博士生4名，硕士生3名。