原发性肝癌标志物Glypican-3细胞膜原位动态修饰的比例荧光探测、化学干预及信号转导机制研究

Glypican-3是一种重要的细胞膜表面蛋白质聚糖，并被鉴定为原发性肝癌的特异性肿瘤标志物，能通过对细胞信号通路的调控促进肝细胞癌变，但其相关作用机制尚未充分阐明。本项目拟基于跨学科团队的深入合作基础，拓展多种基于荧光比例信号的FRET型探针以及基于振动改变发光（VIE）这一我国自主创新光物理学原理的全新分子探针体系，实现Glypican-3侧链肝素聚糖动态脱硫修饰这一与其信号转导过程密切相关生物学事件的细胞原位探测，并进而构建一类可在细胞原位筛选其去硫酸化酶（SULF2）抑制剂的新药筛选平台，通过化学生物学技术与临床资源的有机整合，为GPC-3相关信号转导机制的基础研究提供新的见解，进而为肝癌这一人类重大疾病的精准诊断与个性化治疗提供新的化学工具。

Glypican-3 (GPC-3) belongs to the cell-membrane proteoglycan family. GPC-3 has been identified as a specific biomarker for hepatocellular carcinoma (HCC). However, the precise signal transduction mechanism by which GPC-3 contributes to cancer progression remains largely unexplored. This project integrates research groups with expertise in chemistry, biology as well as medical sciences in order to develop novel chemical tools for the probing and interference of sulfatases that are responsible for the desulfation of the heparan sulfate side chain of glypican-3 (a dynamic process crucial for the signal transduction processes of GPC-3). We sought to develop series of ratiometric fluorescence probes for GPC-3 based on FRET as well as vibration-induced-emission (VIE), which is a brand-new photophysical rationale coined by our group, in order to dynamically monitor the activity of a sulfatase (SULF2) that desulfates the heparan side chain of GPC-3, leading to the activation of Wnt/β-catenin pathway. We will also develop a novel drug-screening platform capable of obtaining bioactive chemical tools in situ that can inhibit SULF2 activity at the cellular level. By integrating the strength of each participating research group and the clinical resources available, we aim to provide an effective strategy for precisely diagnosing HCC and offering personalized therapeutic regimes. With this project we also aim to offer new insight into the GPC-3-relevant signal transdution pathways.