细胞-细胞外基质黏附的分子基础及其调控机制

Cell-extracellular matrix (ECM) adhesion is a fundamental process that is critically involved in embryonic development, tissue integrity, organ functions and the pathogenesis and progression of human diseases. Thus, elucidating the molecular basis underlying cell-ECM adhesion and the mechanisms whereby cells regulate cell-ECM adhesion and related processes (e.g., cell migration) is an important goal of current cell biological research. Our previous studies have shown that three evolutionally conserved proteins, integrin-linkedkinase (ILK), PINCH and parvin, form a ternary complex and localize to cell-ECM adhesions.Subsequently, molecular, cellular and genetic studies by us and others have demonstrated that this evolutionally conserved ternary protein complex (termed as the IPP complex) functions as a key component of the cellular machinery that mediates cell-ECM adhesion and singling.Interestingly, recent studies have revealed that Ras suppressor RSU-1, another evolutionally conserved protein, interacts with the IPP complex. Based on this and other studies, we hypothesize that RSU-1, through its interaction with the IPP complex, plays important roles in regulation of the formation, dynamics, and functions of cell-ECM adhesions and thereby influences cell-ECM adhesion and other related processes including cell spreading and migration. In this project, we will use C. elegans as a model system to determine the functions of RSU-1 in cell-ECM adhesion and related processes in vivo. Furthermore, we will employ state of the art cell biological techniques to define the role of the interaction between RSU-1 and the IPP complex in cell-ECM adhesion, cell spreading and migration. Finally, we will investigate the mechanism whereby the localization and dynamics of RSU-1 and the IPP complex are regulated in cells. These studies will significantly advance our understanding of the molecular mechanism by which cells regulate cell-ECM adhesion and migration, processes that are critically involved in the pathogenesis and progression of many common human diseases.

细胞-基质黏附在各种生物过程和疾病的发生发展中起重要作用。因此，阐明细胞-基质粘附分子基础及其调控机制是现代细胞生物学研究的一个重要内容。我们前期研究发现整合素连接激酶（ILK）、PINCH和parvin形成一个三元蛋白复合物（简称IPP）并在整合素介导的细胞-基质黏附和信号转导中起关键作用。近年来发现Ras抑制蛋白-1（RSU-1）可以与IPP复合物相互作用。根据我们和其他实验室的前期研究，我们推测RSU-1通过和IPP复合物相互作用，可能参与调控整合素介导的黏合斑的形成和功能,从而影响细胞-基质黏附、细胞伸展和迁移等过程。本课题将以线虫为模型从生物整体水平上明确RSU-1和IPP复合物相互作用的功能；同时也将在细胞水平上阐明它在细胞-基质黏附、细胞伸展和迁移中的作用，及其在黏合斑的三维定位、空间分布、动态以及调控机制，从而进一步完善对整合素介导的细胞-基质黏附分子基础和调控机制的认识。

整合素介导的细胞-基质黏附和信号转导在各种生物过程和疾病的发生发展中起重要作用。因此，阐明这一信号通路的分子基础及其调控机制是现代细胞生物学研究的一个重要内容。本课题旨在研究整合素信号通路中一个进化上高度保守的组分—Ras抑制蛋白-1（RSU-1）的功能。我们在细胞水平阐明了RSU-1在细胞-基质黏附、细胞伸展和迁移中的作用，并详细分析了RSU-1缺失对整合素介导的黏着斑动态的影响。此外，还以线虫为模型从生物整体水平上阐明了RSU-1的生理功能。本课题的研究成果进一步完善了对整合素介导的细胞-基质黏附分子基础和调控机制的认识。