NINJ2影响动脉粥样硬化分子机制研究

Atherosclerosis is the most common disease affecting the health of humans，which represent the leading causes of morbidity，mortality and disability worldwide,and caused millions people death every year, However,its genetic and molecular basis is not clear.Discovery of the new biomarker and molecular mechanism of atherosclerosis have become the leading subject of medicine and life science.Aplier The applicant and his colleague found a new soluble protein-sNinjurin2, which was associated with atherosclerosis, and maybe a new biomarker of atherosclerosis.The applicant also found that it may affect atherosclerosis through affecting the cell adhesion,however the detail of its function and mechanism is not clear.To reveal the molecular mechanism of sNinjurin2 affecting atherosclerosis,we will study the details of the formation of sNinjurin,the receptor of sNinjurin , the molecular pathway and the molecular basis of its relationship with atherosclerosis.Our study will clarify the new molecular pathway of process of atherosclerosis, and explore the new intervension strategies.

动脉粥样硬化是世界范围内致死及致残率居首位的疾病，每年引起数百万人死亡，但其遗传和分子机制尚不明确，发现新的生物标志物和分子机制已成为当今医学和生命科学领域前沿课题。申请人课题组首次发现了一种新的可溶性蛋白-sNinjurin2，并发现其基因多态性显著影响动脉粥样硬化发生风险，其血清含量与动脉粥样硬化显著相关，是一种新的生物标志物。研究发现其可能通过调控细胞粘附过程，影响动脉粥样硬化发生，但详细机制目前未知。本研究拟在使用细胞模型和蛋白相互作用等手段，研究sNinjurin对单核-内皮细胞粘附的影响，发现其剪切形成机制，筛选其结合的受体靶点分子，系统性研究sNinjurin2这一内源性活性物质影响动脉粥样硬化发生发展的分子机制，及其对冠心病、脑卒中等疾病发生发展的关系，寻找潜在的生物标志物和干预靶点。

通过本项目的研究，我们发现Ninjurin2基因功能性变异影响中国人群冠心病发生风险，该变异位于调控区内部，可影响转录激活活性。同时，我们还发现，在HUVEC细胞中高表达或是RNAi抑制Ninjurin2表达均会影响单核细胞（THP1）与内皮细胞的黏附。此外，我们通过蛋白质芯片发现，高表达或是RNAi抑制Ninjurin2表达会影响炎症因子和动脉粥样硬化相关细胞因子的表达。再者，我们发现Ninjurin2会介导LPS引起的内皮细胞炎症反应，并可能通过ros信号通路，调控NF-κB的激活和入核。通过酵母双杂交实验和免疫共沉淀等实验，我们发现ninj2可能与自身进行同源结合。通过以上研究，我们初步阐明了ninj2影响动脉粥样硬化的相关分子机制。