血小板衍生生长因子AA在肥胖和糖尿病血管内皮功能障碍中的作用

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, while obesity is a common chronic disease that is associated with type II diabetes and cardiovascular disease. Therefore, it becomes a hot topic to explore their complex pathogenesis and seek effective treatments. Over the past 40 years, platelet-derived growth factor (PDGF) has been studied in many fields, such as in development, cancer, atherosclerosis, pulmonary arterial hypertension, vascular inflammation and wound healing. But the role of PDGF in vascular endothelial function is rarely studied in diabetes. Previous study showed that PDGF-AA was highly expressed in the plasma of type II diabetic patients, and PDGF-AA could impair endothelium-dependent vasodilatation. In vivo knockdown of PDGF-AA could effectively improve endothelial function in diabetic db/db mice, indicating that the interference of PDGF-AA signaling pathway may play a role in the protection of vascular endothelial function. As endoplasmic reticulum (ER) stress is one of the main inducers of type II diabetes, this project explores whether PDGF-AA enhances ER stress to impair vascular endothelial function; further study will be made to reduce ER stress to inhibit PDGF-AA impairment; finally target genes in PDGF-ER stress signaling will be explored for the treatment of vascular endothelial dysfunction.

糖尿病是一种以高血糖为特征的代谢性疾病, 而肥胖作为一种普遍的慢性病常常伴随着II型糖尿病和心血管疾病的发生。因此，探究其复杂的发病机理以及寻求有效的治疗途径已经成为当今的研究热点。在过去的40多年里，血小板衍生生长因子（PDGF）在发育、癌症、动脉粥样硬化、肺动脉高压、血管炎症、伤口愈合等领域研究甚多，但其对糖尿病血管内皮功能的作用尚未研究透彻。前期实验表明PDGF-AA在II型糖尿病病人血浆中高表达，并且损伤血管内皮依赖性舒张。在体敲低PDGF-AA有效改善糖尿病小鼠内皮功能, 提示干扰PDGF-AA信号通路可以起到保护血管内皮功能的作用。 由于内质网应激是II型糖尿病的主要诱因之一，本课题首先探索PDGF-AA是否是通过增强内质网应激来损伤血管内皮功能；进一步研究通过干预内质网应激来抑制PDGF-AA的功能；最后探究PDGF-内质网应激信号通路相应靶点来治疗血管内皮功能障碍。

糖尿病是一种以高血糖为特征的代谢性疾病并伴随着血管功能障碍，患者表现为伤口极难愈合，其机理复杂且相关作用机制并未探究清楚。前期研究表明PDGF-AA在II型糖尿病病人血浆中高表达，并且损伤血管内皮依赖性舒张（EDR）。在体敲低PDGF-AA可有效改善糖尿病小鼠内皮功能。课题进一步研究发现PDGF-AA会通过增强内质网应激来损伤血管内皮功能; 通过干预内质网应激可抑制PDGF-AA的血管内皮损伤作用。课题同时研究发现PDGF-AA的诱导蛋白BMP4对于促进糖尿病伤口愈合有潜在疗效，可通过上调FGF10等蛋白表达加速伤口愈合。综上，本课题初步证明了PDGF-内质网应激信号通路在糖尿病血管内皮功能障碍中的作用和相关机制，同时初步证实了BMP4在加速糖尿病伤口愈合中的作用。