微泡产生过程的能量学和动力学以及微泡导致细胞损伤的关键因素研究

Microvesicles are lipid vesicles in submicrometer scales released from activated or apoptotic cells. In pathologic conditions such as diabetes mellitus and cardiovascular disease, the number of microvesicles in blood plasma is highly increased, which in return stimulates and induces injury to the other normal cells and hence aggravates the diseases quickly. Although the primary generation mechanism of microvesicles has been unveiled through the previous basic medical researches, the purely medical experiments can hardly go deeply. In this project the scientific questions as follows are proposed from the viewpoint of fundamental physical principles and will be solved with the aid of the latest physical equipments and the basic medical experiments: (i) the generation mechanism of endothelial microvesicles which includes the free energy changes during the blebbing and shedding of microvesicles as well as the relationship between the number of microvesicles and the strength of stimulating factors is fully investigated; (ii) the shapes and size distributions of microvesicles as well as the relationship between them and the contents of microvesicles are accurately measured and quantitatively interpreted; (iii) the mechanism for microvesicle-induced injury to normal cells which includes the key role that the content of microvesicles play in, the direct consequence of injury to normal cells, and the free energy changes during the fusion between microvesicles and cell membranes is primarily investigated. This research will be helpful to provide clues for determining the whole pathway of microvesicle-induced injury to normal cells, the theoretical basis and new insight for investigating the pathogenesis and clinical diagnosis of diabetes mellitus and cardiovascular disease. This project will also be a good example for the application of physical principles in medical researches.

微泡是激活或凋亡细胞释放的一种亚微米尺度的脂质膜泡。在病理条件下，如在糖尿病和心血管疾病中，血浆中的微泡数量显著增加，微泡水平升高又反过来刺激其他正常细胞而导致损伤，加剧病情发展。尽管前期基础医学研究初步揭示了微泡的产生途径，但单纯医学实验无法使研究更深入。本项目试图从基本物理原理出发提出问题，并借助物理学的最新观测手段，结合基础医学实验深入探讨血管内皮细胞来源微泡的产生机理（包含微泡释放过程自由能的变化以及微泡数量与刺激信号强度的关系等），精确观测微泡形态和尺寸分布并定量阐明它们与微泡内容物的关系，初步探索微泡导致正常细胞损伤的机理（包含微泡内容物的关键作用、微泡导致细胞损伤的直接后果以及微泡与膜融合的自由能变化等）。该项目的完成将为今后确定微泡导致细胞损伤的完整途径提供线索，为研究糖尿病和心血管疾病的发病机制和临床诊断提供理论依据和新思路，为将物理学方法应用于医学研究提供范例。

微泡是激活或凋亡细胞释放的一种亚微米尺度的脂质囊泡。本项目试图从基本的物理原理出发，结合基础医学实验探讨血管内皮细胞来源微泡的产生机理（包含微泡释放过程中的自由能变化以及微泡数量等），观测微泡形态和尺寸分布并定量阐明它们与微泡内容物的关系，初步探索微泡导致细胞损伤的机理，为研究高血压和心血管疾病的发病机制和临床诊断提供理论依据。通过本项目的研究，我们基于Helfrich自发曲率弹性理论阐明了微泡产生途径中物理步骤的自由能变化，分析了分裂时颈端附近膜的曲率满足的连接条件，得到了微泡的平衡形状方程，给出了释放的微泡处于稳定的尺寸范围。我们发现CD144+/CD62E+表型的内皮细胞来源微泡是监测高血压伴高血脂症内皮损伤的重要特异性标记物，发现CD51+内皮细胞微泡水平的显著增高是高血压伴肥胖患者的内皮细胞损伤特征。我们对氯吡格雷治疗高血压患者进行了细胞微泡的分析研究，发现高血压患者CD42b+小血板微泡数明显低于健康人。该结果表明高血压外周血中的小血板微泡对研究血小板微泡在高血压疾病中的病理生理机制以及作为一种新的标志物非常有意义，同时提示氯吡格雷可以降低冠心病的风险是通过抑制小血小板微泡而不是大血小板微泡的产生而实现的。该结果为一些药物（如氯吡格雷）控制高血压和防治并发症的疗效观察提供了科学依据。