基于钒化合物对胰岛素信号通路的调控机制研究其对阿尔茨海默症的潜在防治作用

It has been considered that the antidiabetic effect of vanadium compounds can be attributed to their regulation of insulin signaling pathway. However, the underlying mechanisms and the working species are still controversial and become the bottleneck of their further development and application. Firstly, the current project aims to investigate the interrelationships between the transformation of oxidation states, the generation of reactive oxygen species and the regulation of insulin signaling pathway of various vanadium compounds with differential chemo-physical properties (oxidation states, coordination environment and stabilities, etc.) in the insulin-targeted cell types. The characteristics of the regulation of cellular redox state by vanadium compounds will also be elucidated. Secondly, based on the fact that the dysfunctional insulin signaling pathway is a critical pathological link shared by both diabetes and Alzheimer’s disease (AD), the current study will further explore whether the studied vanadium compounds improve the symptoms of transgenic AD mice and determine whether the improvement is associated with the regulation of insulin signaling pathway. The results obtained in this investigation may help to study how to block the connection between the above two diseases and also help to design new vanadium compounds with higher efficacy and lower toxicity based on mechanistic studies as well as provide important foundations for their potential application in the prevention, treatment or delay of the development or progression of the two related diseases. This project reflects the cross-discipline integration in research ideas and methods. The results are expected to promote the development of cell inorganic chemistry.

钒化合物的抗糖尿病效应被认为与其调控胰岛素信号通路有关，但其作用机制以及活性物种仍存在争议，已成为对其进一步研发应用的瓶颈。本项目拟首先在细胞水平通过选择具不同理化性质（氧化态、配位环境和稳定性等）的典型钒化合物，研究其在胰岛素靶细胞中的氧化态的转变、引起活性氧物种的产生和调控胰岛素信号通路间的相关性，揭示钒化合物调控细胞氧化还原状态的特点。其次，基于胰岛素信号通路障碍是糖尿病以及阿尔茨海默病（AD）这两种疾病共同的关键病理环节，进一步考察钒化合物是否能改善转基因AD小鼠的症状，并确定这种改善是否与其调控胰岛素信号通路有关。本项目的研究结果将有助于研究如何阻断上述两种疾病间的联系，也有助于基于机制设计合成具有高效低毒的钒化合物，从而预防、治疗或推迟两种疾病的发生或发展，为后续探讨其在临床中的应用潜势奠定重要基础。本项目充分体现了学科的交叉融合，将有助于推动细胞生物无机化学学科的进一步发展。

本项目立足于钒化合物调控的胰岛素信号通路作为出发点，在细胞以及动物水平上，基于从内在相互联系的病理环节中寻找防治针对多种疾病的药物这一新思路，研究了具抗糖尿病活性的钒化合物在阿尔茨海默病防治以及神经保护中的作用。主要研究进展包括如下三方面：（1）利用9月龄的三转基因AD小鼠模型（3xTg-AD）的研究表明，钒化合物可改善转基因AD小鼠的AD病理症状，可提高小鼠的背景关联记忆和空间学习能力；并可改善AD小鼠的糖代谢，同时保护神经元突触。研究还表明，钒化合物可降低PTP1B的表达，增加胰岛素的敏感性，激活胰岛素信号通路，从而降低tau的过度磷酸化。（2）在C2C12-HT22骨骼肌-小鼠海马神经元细胞肌脑交流模型的研究显示，钒化合物可作为一种运动模拟药物，在效应和机制上模拟有氧锻炼对骨骼肌糖脂代谢、能量代谢和分泌功能的改善。其中，钒化合物引起骨骼肌细胞分泌的IL-6在对损伤的神经元细胞的保护中起到了重要作用。（3）以STZ诱导的糖尿病大鼠以及人肾小管上皮细胞HK-2为细胞模型为模型的研究表明，钒化合物引起的细胞氧化还原状态的改变是其同时发挥药理和毒理作用的原因，此结果提示可通过有效选择针对不同ROS来源的抗氧化剂，在不影响其发挥生物学活性的同时降低钒化合物的潜在毒性。本项目的研究结果将助于合成具有高效低毒的钒化合物，降低其毒性风险；为后续探究钒化合物作为潜在的阿尔茨海默病防治以及神经保护的药物奠定重要基础。同时在研究思路和方法上都充分体现了学科的交叉融合，将有助于推动学科的进一步发展。