活细胞实时原位脂质定量检测方法研究鞘磷脂循环在肿瘤细胞凋亡过程中的分子机制

This project will focus on the core question of the Program about "biological macromolecular dynamic modification and chemical intervention" on biological macromolecules dynamic modification of chemical markers and detecting technology. In view of the technical challenges of the in-situ real-time lipid quantitative detection in live cells, we will develop a series of lipid fluorescent sensors with high specificity and sensitivity, and then establish high-precision lipid quantification method for real-time in-situ detecting lipid content and dynamic distribution in live cells. This will be an efficient and high-fidelity way to convert the information of lipid molecules to measurable signal. The intermolecular transformation of lipid molecules related to sphingomyelin circulation and the turnover mechanism of lipid molecules in the inner and outer layers of cell membrane are systematically studied to reveal the molecular mechanism of sphingomyelin circulation in the process of tumor cell apoptosis. This extremely challenging research is expected to better understand the pathogenesis of the disease and provide new therapeutic strategies for cancer. In this project, by measuring the concentration of lipid molecules in living cells by spatiotemporal interpretation is a key step in understanding the myriad lipid-mediated biological processes and developing new strategies for the prevention and treatment of human diseases caused by the dysfunction of membrane-associated processes. With strong interdisciplinary nature and good research background, it is expected to contribute to the overall goal of the Program.

本项目将围绕“生物大分子动态修饰与化学干预”重大研究计划的生物大分子动态修饰的化学标记与检测技术这一核心科学问题，针对目前活细胞实时原位脂质定量检测存在的技术挑战，发展高特异性、高灵敏度的脂质荧光探针，将活细胞内脂质分子相关信息高效、高保真地转换成可测量信号。建立高精度活细胞实时原位脂质定量检测方法，对鞘磷脂循环相关脂质分子间相互转化及脂质分子在细胞膜内外层间翻转机制进行系统研究，揭示鞘磷脂循环在肿瘤细胞凋亡过程中的分子机制，更好地理解疾病的发病机理，为癌症提供新的治疗策略。这一极具挑战性的研究通过时空解译的方式测定脂质分子的浓度，是理解许多脂质介导的生物过程的关键一步，对预防及治疗由膜相关过程功能失调引起的人类疾病具有重要意义。项目组包含青千1位，其他成员均具有交叉学科背景，研究基础好，有望为实现总体目标作出贡献。

本项目围绕“生物大分子动态修饰与化学干预”重大研究计划的生物大分子动态修饰的化学标记与检测技术这一核心科学问题，针对鞘磷脂循环在肿瘤细胞凋亡过程中的分子机制研究，发展了多种基于蛋白结构域的生物探针，用于鞘磷脂循环相关脂质分子的原位识别和检测；开发了基于单颗粒示踪的活细胞内实时原位定量检测方法，用于与细胞胞吞过程密切相关的pH值及脂质的原位定量检测；基于细胞自噬与凋亡之间的关系，开发了可以诱导肿瘤细胞凋亡的纳米药物用于肿瘤治疗。本项目结合化学生物学、分析化学及细胞生物学等多学科交叉手段，充分发挥学科集成优势，实现了对活细胞中脂质分子相互转化及脂质分子在细胞膜内外层间翻转机制的时空动态研究，为癌症提供新的治疗策略。受疫情影响，国际国内交流由线下转为线上方式，保障深入学术交流。在学科交叉、合作攻关等方面形成了完整的体制和机制，既保证了本项目预期研究目标的圆满实现，也为项目组进一步开展交叉合作研究奠定了良好基础。项目执行期间，在国际重要学术刊物上，包括Angewandte Chemie International Edition，Nano Letters，Nano today， Analytical Chemistry，Small等，发表SCI论文18篇，申请专利4项，已授权1项。培养博士生2名，硕士生2名。

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