新型甲醛荧光探针的开发及其在疾病模型中的成像应用研究

Formaldehyde, as the simplest aldehyde, is not only widely used in chemical industry, but also endogenously produced and maintained in living systems via enzymatic pathways. While adequate levels of endogenous formaldehyde mediate normal physiological processes, elevated production of formaldehyde in living systems has been implicated in the pathology of many diseases, such as cancer, Alzheimer’s, stroke, diabetes, and liver disorders, due to its potent ability to cross-link DNA, RNA, and protein. However, the precise roles of formaldehyde in pathologies have not been well-understood, probably due to lack of a robust detection and imaging method in live biological samples. This proposal aims to solve this technical limitation by developing a series of new small-molecule fluorescent probes for formaldehyde detection and imaging in live biological specimens. Specifically, in this proposal we will develop a general and modular formaldehyde probe design strategy that relies on its reaction with homoallylic amine derivatives. We will systematically optimize the homoallylic amine structures for formaldehyde sensing and then construct various formaldehyde probes with distinct photophysical and intracellular properties, such as different colored probes, organelle-targeted probes, and FRET-based ratiometric probes. These new probes will be thoroughly characterized in live cells for intracellular imaging of formaldehyde and also be applied to animal disease models such as breast cancer and Alzheimer’s to directly visualize the endogenous production of formaldehyde during progression of these diseases. This project will not only generate powerful molecular imaging tools for studying the biology of formaldehyde under physiological and pathological contexts, but also provide new insights into the pathological roles of formaldehyde in breast cancer and Alzheimer’s disease, thus shedding light on further studies about formaldehyde as a disease biomarker and potential drug intervention target.

甲醛不仅是一种重要的工业品，并且还能在生物体内通过酶系统介导的正常生理过程产生。适当浓度的内源甲醛在正常的生理活动中发挥重要的作用，然而其过量产生却被暗示与一系列疾病的发生过程有关，包括癌症、阿尔茨海默症、中风和糖尿病等。由于缺乏有力的生物样品中成像检测方法，甲醛与这些疾病发生过程的具体关系仍不清楚。基于申请人的研究经历及前期的初步工作，本项目拟开发一个通用的可模块化的甲醛荧光探针构建策略，并制备一系列新型的具有各种荧光颜色、特异光学性质及细胞内行为的甲醛探针；然后对它们在细胞内成像甲醛的性能进行彻底地表征和优化，进而用于动物疾病模型中（如癌症和阿尔茨海默症）以成像分析内源甲醛在疾病发生过程中的产生和机制。本项目不仅将提供有力的生物成像探针工具用于甲醛的生物学研究，并且有助于揭示甲醛与癌症和阿尔茨海默症的病理关系，从而为进一步探索内源甲醛作为疾病诊断标志物及潜在药物干预靶标打下初步基础。