糖尿病患者HDL中所含S1P等生物活性类鞘磷脂对血管内皮细胞代偿性保护功能研究

With the help of previous funding, we published 8 papers (7 with me as corresponding author). We previously found normal HDL can up regulate COX2, and release PGI-2, which have protective effects to endothelial cells. Not only S1P but also apoA-I has this function. And, we found diabetic HDL has more significant protection effects in inducing COX2 expression and PGI-2 release, which is due to the increased level of S1P level in diabetic HDL, not modification of apoA-I. We also used specific inhibitor of S1P receptor to prove this phenomenon. The precursors of S1P are ceramide and sphingosine, which has negative effects on endothelial cells. We want to study how S1P can be increased in diabetic HDL; how S1P keep the balance of function with ceramide and sphingosine; and the quantity and activity of enzymes related to the level of S1P have been changed in diabetes. We will use different approaches including clinical samples, mass spec. technology, diabetic mouse model, etc. to study S1P and other sphingomyelin-like lipids in diabetic HDL.

我们发现正常的HDL提高COX2表达和PGI-2释放的原因除了所含的鞘磷脂S1P外，还有apoA-I。对于糖尿病HDL，我们发现糖尿病HDL具有更显著上调COX2表达和PGI-2释放，而这些功能与apoA-I的修饰无关，而是由于S1P大量汇集造成，我们通过S1P特异性的受体抑制剂等都证明了这推论。在前期青年基金的支持下发表SCI文章13篇（责任作者10篇）。由于S1P代谢中有两个很重要的前体，ceramide和sphingosine。这两个前体却与S1P不同，他们对内皮有破坏作用。我们的研究将集中研究糖尿病HDL中S1P如何增加以及糖尿病后期减少的原因，并且S1P是如何与它的前两个前体形成一种平衡。同时我们将进一步研究在糖尿病状态下，S1P的量的改变是否涉及到与它代谢密切相关的3个合成酶或分解酶的量与活性。我们将结合临床样品，代谢生物质谱技术，糖尿病小鼠模型等进行研究。

我们对S1P与HDL以及糖尿病血管功能展开研究。我们发现HDL可以促进脂肪干细胞的增殖；通过脂肪干细胞膜表面S1P1受体，促进细胞周期蛋白D1和细胞周期蛋白E的表达量上升，并且下调细胞周期阻抑蛋白p21和p27的表达，促进细胞周期进程，进而实现促进细胞增殖的效果，2015发表在Stem Cell Research & Therapy上。疾病状态下的HDL对比正常HDL功能会发生变化，我们通过已建立的脱脂方法，将HDL的蛋白质与不同脂类分开，结合代谢组学生物质谱技术，发现了导致COX2显著上调的HDL脂类为S1P。通过重组我们确认了S1P在其中所发挥的作用。我们还应用了S1P受体的特异性抑制剂验证了此功能。我们证实在糖尿病发展的初期S1P在HDL中的含量增加使得糖尿病患者HDL在动脉粥样硬化发生的病理生理过程中所发挥的对内皮细胞代偿保护作用，随着糖尿病的发展代偿性保护功能逐渐减弱。2014年发表在Cardiovasc. Diabetol...已经发表SCI责任作者34篇，新接受SCI责任作者一篇，其中影响因子大于等于5的有10篇，总SCI引用累积接近2000。获得省部级奖一项，申请专利3项，获得国家CFDA体外诊断试剂批号一项。发表与接受的大于等于5的作为责任作者的SCI杂志包括：Advanced Functional Materials（IF=12.1）；Free Radical Biology and Medicine；Redox Biol.（2篇）；ACS APPL MATER INTERFACES；J Am Heart Assoc；BBA-Molecular and Cell Biology of Lipids；International Journal of Cardiology；Nanoscale；Molecular Cancer。