糖尿病血管内皮损伤的新机制：CTRP9/N-cadherin/β-catenin通路受损致血小板异常激活

血管内皮损伤是糖尿病多种心血管并发症的共同始动因素。已知血小板过度激活可致内皮损伤，但糖尿病何以致血小板过度激活尚不明确。申请者新近报道新脂肪因子CTRP9具有明确的抑血小板活化功能，糖尿病血浆CTRP9降低与血小板活化程度明显负相关。合作者首次发现N-cadherin是CTRP9在干细胞的特异受体，通过β-catenin通路调节细胞功能(Circ Res 2020)。预实验发现，血小板表达N-cadherin但不表达CTRP9另一结合蛋白adipoR1。本研究将利用基因与药物干预手段，结合离体分子机制研究与在体疾病模型验证，揭示CTRP9/N-cadherin/β-catenin通路在血小板功能调节中的关键作用及机制，验证CTRP9降低而导致的N-cadherin/β-catenin通路失活是糖尿病血小板过度激活进而导致内皮损伤重要机理的科学假设，为保护糖尿病血管内皮寻求新的干预靶点。

Vascular endothelial injury is a common initiator of cardiovascular complications in diabetes mellitus. Platelet excessive activation is known to cause endothelial injury, however, the mechanisms involved in platelet activation caused by diabetes are still elusive. Recently, we have reported the adipokine CTRP9 has a clear function of inhibiting platelet activation, and the decrease of plasma CTRP9 in diabetes mellitus is negatively correlated with the degree of platelet activation. The collaborators first identified N-cadherin as a specific receptor for CTRP9 in stem cells, regulating cellular function through β-catenin pathway (Circ Res 2020). Preliminary experiments showed that platelets express N-cadherin but not AdipoR1, another binding protein of CTRP9. This research will reveal the key role of CTRP9/N-cadherin/β-catenin pathway in platelet function regulation by utilizing the gene methods and medicine intervention combined with the molecular mechanism studies in vitro and disease model in vivo, and verify the hypothesis that excessive platelet activation caused by lower CTRP9 levels and impaired N-cadherin/β-catenin pathway greatly contributes to diabetic endothelial injury, which might throw a new light on therapeutic targets for protecting against vascular endothelial injury.