Basement membrane assembly is required not only for tubulogenesis, but also for maintenance of epithelial tubular structures containing polarized cells. Basement membranes are thin sheet-like structures assembled through complex interactions among the major components, laminins, collagen IV, perlecan, and nidogens. Several groups have shown that the lack of laminins disrupts formation of basement membranes in vitro and in vivo. However, although a laminin self-assembly model involved in formation of basement membrane has been hypothesized, the details remain to be defined. We will first aim to clarify the mechanism of basement membrane assembly using in vitro models such as cyst and tube formation. We have also focused on the functions of laminins, which provide cell adhesion activity to the basement membrane. Static cell adhesion to basement membrane is essential to maintain epithelial tubular structure. Therefore, the imbalance of cell adhesion to basement membrane in epithelial tubes could be involved in pathologic features, such as tumor invasion. Another major purpose of this project is to clarify the role of basement membrane in tumor invasion.

We have succeeded in producing recombinant laminins and related proteins. To achieve our research purpose, we will try to clarify the roles of laminins in basement membrane assembly using the recombinant proteins in a three dimensional culture system. We have also investigated the functions of laminins in influencing cell adhesion and migration in vitro. In this project we will investigate the molecular mechanism of cell adhesion to basement membrane in epithelial tubes. Moreover, we will examine whether disruption of basement membrane assembly and cell adhesion in epithelial tubes are involved in tumor cell invasion or in other diseases.

Research achievements deriving from this project will contribute to our understanding not only of basement membrane assembly, but also of how it coordinates epithelial polarity in tubular structures. In addition it will provide new insights into how tumors invade into or through basement membranes. Moreover, our results regarding laminin structure can be utilized for tailoring biomaterials to achieve specific cellular responses in epithelial tubes.