The fibronectin receptor is one of a set of cell surface heterodimers involved in adhesion. These molecules have been implicated in morphogenesis, hematopoietic differentiation, hemostasis, inflammation, metastases and perhaps atherogenesis Deficient cell surface expression of members of this group have been associated with the hematologic disorders Glanzmann's thrombasthenia and leukocyte adhesion deficiency. No disease has yet been associated with deficient fibronectin receptor expression. This may be because of its critical role in embryogenesis. Acquisition or loss of cell surface fibronectin receptor accompanies hematopoietic differentiation along different pathways. Cell migration, morphogenesis and tumor metastases can be blocked by F(ab')2 fragments of antibody to the fibronectin receptor. Fibronectin receptor variations have been shown from different tissues of a single animal. These data suggest that the fibronectin receptor is involved in cell migration and localization.
The aim of this research proposal is to define the role of the fibronectin receptor in normal and neoplastic cell migration. In phase I, I plan a course of formal study in biochemistry, immunogenetics, tumor biology and molecular genetics. Research goals for phase I are the generation of antiserum to the murine fibronectin receptor. Using this antiserum, I will determine fibronectin receptor biochemical differences in murine tumor cell lines with different migration patterns. Finally, the functional and physiologic consequences of these modifications will be investigated. Using the reagents generated in phase I, in phase II I plan to clone the alpha and beta receptor subunits from one of the cell lines. DNA sequencing will be used to confirm the identity of the clones. The cloned subunits will be serially transfected into a human B lymphoid cell line. Finally, the migration of these double transformants will be observed in nude mice. This research will add greatly to our understanding of the functional role of the fibronectin receptor. While pursuing these scientific goals, I will be developing the skills necessary for an independent research career.
