线粒体作为氧化石墨烯生物效应作用靶点的热力学诠释及其分子机制研究

Nanomaterials have direct relationship with reactive oxygen species of mitochondria and regulation of cell apoptosis. Graphene oxide (GO) nanomaterials have unique properties and a lot of biomedical applications, but its biological effects and toxicity are still not clearly understood, especially on the level of cell organelle. In this project, the multiple functionalized GO are selected as the object of research and the mitochondria isolated from rat liver are used as biological models. The thermodynamics and dynamics properties of their interaction will be investigated by using modern microcalorimetric technique, transmission electron microscopy, spectroscopic methods, electrochemical methods, biochemical analysis techniques and oxygen electrode. Structure-activity relationship between GO and living metabolism dynamic process of mitochondria will be established, and some important thermodynamic parameters and kinetic parameters will also be obtained. With the help of thermokinetics, the biological effect and mechanism of functionalized GO will be investigated from structure and function on the level of mitochondria. The thermokinetic model of the effect of functionalized GO on cell apoptosis will be established, and a lot of thermokinetic properties will be obtained. Also, the mitochondrial conformation, respiration function, membrane structure, membrane penetration transition, membrane fluidity and enzyme activity will be investigated. The influence path and the molecular mechanism of the structure of mitochondria affected by GO will be revealed deeply, and the mechanism of GO involved in the biochemical process will be further understood and revealed. The novel method of GO biological effects will be developed. These research will provide quantitative data and theoretical basis for design of GO and for thorough application of GO in biomedical fields.

众多研究表明，纳米材料毒性活性氧机制以及纳米颗粒诱导细胞凋亡路径都和线粒体存在直接的关系。当前针对氧化石墨烯等纳米材料生物效应多集中在生物个体、细胞和生物大分子等水平上，但在亚细胞层次上的研究仍处于起步阶段。本项目拟以线粒体为靶点，采用生物微量热、显微、光谱、电化学、生化分析和呼吸耗氧等多种研究手段和技术相结合，从结构和功能上系统研究功能化氧化石墨烯对线粒体代谢动态过程的影响及其机制，建立相互作用热动力学模型；从线粒体形态、呼吸功能、膜结构、钾氢离子的渗透性、膜电势、渗透转换孔开放、膜流动性、酶活性等方面，探讨功能化氧化石墨烯等纳米材料诱导细胞凋亡成因，进一步揭示和认识氧化石墨烯参与生命动态化学过程的机制；从宏观到微观建立氧化石墨烯生物效应研究的新方法，为氧化石墨烯等纳米材料的设计及其在生物医学领域的深入应用提供定量数据和理论依据，促进学科在高水平、深层次上的交叉渗透。

众多研究表明，纳米材料毒性活性氧机制以及纳米颗粒诱导细胞凋亡路径都和线粒体存在直接的关系。当前针对氧化石墨烯等纳米材料生物效应多集中在生物个体、细胞和生物大分子等水平上，但在亚细胞层次上的研究仍处于起步阶段。本项目以线粒体为靶点，采用生物微量热、显微、光谱、电化学、生化分析和呼吸耗氧等多种研究手段和技术相结合，从结构和功能上系统研究功能化氧化石墨烯对线粒体代谢动态过程的影响及其机制，建立相互作用热动力学模型；从线粒体形态、呼吸功能、膜结构、钾氢离子的渗透性、膜电势、渗透转换孔开放、膜流动性、酶活性等方面，探讨功能化氧化石墨烯等纳米材料诱导细胞凋亡成因，进一步揭示和认识氧化石墨烯参与生命动态化学过程的机制；从宏观到微观建立氧化石墨烯生物效应研究的新方法，为氧化石墨烯等纳米材料的设计及其在生物医学领域的深入应用提供定量数据和理论依据，促进学科在高水平、深层次上的交叉渗透。该项目的相关研究工作共发表SCI论文27篇，其中二区以上论文19篇，获授权国家发明专利11件，获省级科研奖励4项。项目执行期间共联合培养博士研究生6名、硕士研究生16名，有4名硕士毕业生继续攻读博士学位。