The long term aim of this project is to understand the molecular basis of cell-matrix adhesion, its effects on cell structure and behavior and the nature of alterations occurring in oncogenic transformation and related physiological/pathological systems.
The specific aims are to: 1. Use recombinant fibronectin (FN) constructs and proteins to investigate different cell interaction sites within FN, the receptors for them, and their roles in the behaviors of various cell types. 2. Analyze in detail the structure-function relationships of certain domains of FN using molecular genetic and biochemical approaches. 3. Particular attention will be paid to those segments of FN which are alternatively spliced and differentially expressed. 4. Investigate the control of alternative splicing of FN pre mRNA both in vivo and in vitro systems. 5. Study the functions and interactions with FN and with cytoplasmic proteins, including cytoskeletal proteins, of the various integrin subunits which make up FN receptors. These questions will be approached by molecular genetic and biochemical methods. 6. Investigate the interactions of the cytoskeletal protein talin with the cytoplasmic domains of integrins and with other cytoskeletal proteins. 7. Particular attention will be paid to the nature of alterations in integrin expression, function and interactions with FN and cytoplasmic proteins in oncogenically transformed cells. These studies should provide new insights into the molecular basis of cellular adhesion and its contribution to the structure and behavior of normal cells. The results will have relevance for understanding of embryological development, hemostasis, thrombosis, wound healing, inflammation, invasion and metastasis. All these processes involve cell adhesion to extracellular matrices and molecules identical or closely related to those under study in this project.
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