Cell adhesion and migration are critical biologic events during the development and regeneration of periodontal tissues. Fibronectin (FN) is a cell adhesion molecule that has important functions in adhesion, migration, proliferation and differentiation of cells. Important ligand-receptor interactions are controlled by the physical relationships of the cell-binding and synergy sites in FN. In addition, pre-mRNA of FN transcript undergoes alternative splicing to produce numerous functional isoforms of the molecule. Preliminary data suggests that inclusion/exclusion of the spliced domains EIIIB/EIIIA may have an impact on the adhesion and migration of cells. The proposed studies are designed to test the hypothesis that during wound healing/tissue regeneration, isoforms of cellular FN (cFN) regulate the quality of cell adhesion to facilitate the migration and eventual differentiation of cells. The First Specific Aim will evaluate the ability of the EIIIB and/or EIIIA positive isoforms of FN to enhance the migration of cells. A detailed analysis of the mechanisms influencing the modulated cell adhesion and migration of cells will be undertaken. We hypothesize that EIIIB and EIIIA positive isoforms of FN will have modulated cell adhesion useful in enhancing cell migration. The Second Specific Aim will examine in detail, periodontal tissue/bone regeneration in mice that have conditional knockout of plasma FN (pFN) but continue to have expression of cellular FN (cFN) in the healing tissues. Plasma FN (pFN) is abundant in the provisional matrix in wounds and can hinder the analysis of the functions of cFN (EIIIB/EIIIA+ve) synthesized by cells in and around the wounds. We will use mice where the pFN is conditionally knocked out with the cFN expression by cells in healing wounds intact. We hypothesize that bone and periodontal tissue regeneration in mice expressing only cFN (EIIIB/EIIIA+ve) may in fact be enhanced. The Third Specific Aim will evaluate the effects of recombinant fragments of FN that include domains EIIIB and EIIIA and small synthetic peptides on enhancing the migration of cells and wound healing/tissue regeneration in mice with pFN conditionally knocked out. We hypothesize that EIIIB and EIIIA positive isoforms of FN as well as small peptides representing biologically active sites can be effective in enhancing wound healing/tissue regeneration. Data from these studies should provide important information on the biologic functions of spliced domains EIIIB and EIIIA of FN that can be used to design recombinant proteins or peptides to enhance regeneration and wound healing.
| Bencharit, Sompop; Cui, Cai Bin; Siddiqui, Adnan et al. (2007) Structural insights into fibronectin type III domain-mediated signaling. J Mol Biol 367:303-9 |
