应用膜蛋白纳米组装研究EGFR/HER2过表达致癌的分子机理与结构

项目名称： 应用膜蛋白纳米组装研究EGFR/HER2过表达致癌的分子机理与结构

项目编号： No.31470730

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 米立志

作者单位： 天津大学

项目金额： 85万元

中文摘要： EGFR(表皮生长因子受体）及其同源蛋白HER2, HER3, HER4是调控细胞生长与分化的重要酪氨酸激酶受体。这些受体的突变或过表达将引起激酶活性的失调，并导致包括肺癌与乳腺癌在内的各种癌症。因此，这些受体是治疗癌症的重要药物靶底。目前对于EGFR激酶突变所引起的激酶活性失控及其致癌机理已有较深入地研究，但对于由EGFR或HER2过表达所引发的跨膜信号变化，相应的分子结构，及由此导致的癌症发生与耐药性产生的分子机理均所知甚少，在临床上也缺乏有效的靶向性药物或治疗窗口。本项目旨在应用纳米磷脂盘技术在体外脂膜环境下重构EGFR或HER2过表达的功能性膜蛋白复合物，并以此为基础应用电镜、生物物理、生物化学和细胞生物学综合手段研究由EGFR或HER2过表达引起的跨膜信号传导失调及其致癌的分子结构与机理。我们还将进一步阐明针对这一失调信号的抗体药物和抗体药物/激酶抑制剂结合的组合疗法的作用机制。

中文关键词： 膜蛋白；电镜；纳米组装；激酶受体；癌症

英文摘要： Epidermal growth factor receptor (EGFR) and its homologs (HER2,HER3, and HER4) belong to receptor tyrosine kinase (RTK) superfamily. They regulate important cellular functions, including cell growth, differentiation,and proliferation. Dysregulation of these receptor transmembrane signaling, either by mutation or by overexpression, leads to tumorgenesis. Therefore, they are validated therapeutic targets in the treatment of various cancers, such as lung and breast cancer. Although significant progress had been achieved in understanding the basis for oncogenesis associated with EGFR kinase mutation, less is known about how the transmembrane signaling is dysregulated by EGFR/HER2 overexpression, and how EGFR/HER2 overexpression contribute to oncogenesis and drug resistance. This proposal aims to 1) apply newly developed lipid nanodisc technique to functionally reconstitute high density EGFR or HER2 complexes into lipid membrane, and 2) study the basis for following open questions: how does EGFR/HER2 overexpression cause the dysregulation of receptor transmembrane signaling? how do therapeutic antibodies targeting EGFR or HER2 extracellular domain modulate receptor transmembrane signaling? and how do these antibodies coordinate with kinase inhibitors through lipid membrane in combinational therapy? These studies are of conceptional importance in understanding the biology of RTK transmembrane signaling. They also have implications in novel therapeutic development targeting EGFR or HER2 overexpression in cancer.

英文关键词： receptor tyrosine kinase;lipid nanodisc;transmembrane signaling;cancer;EM