Fibronectin peptides for treatment of burns

DESCRIPTION (provided by applicant): There are more than 1 million burns each year in the US, resulting in 700,000 emergency department visits, 45,000 hospital admissions, and 4,500 deaths. Burns are dynamic injuries characterized by progressive extension of the injury over the first few days. Progression of partial thickness burns to full thickness injuries is associated with increases in mortality, wound sepsis, and scar formation. Methods aimed at preventing burn progression have been the focus of intense research but these results have been disappointing. In fact the unmet challenge of burn treatment is development of a therapy that limits injury, speeds healing and reduces scarring. Discovery of novel methods to successfully address this challenge would be a major advance in the care of patients with burns. Over the past decade the Clark laboratory has made several critical observations about new tissue formation in wounds. These in vivo investigations stimulated the development of a novel in vitro model of cell migration across matrix boundaries as would be found in early healing wounds. The assay has also been utilized to screen new matrix materials for their ability to support cell migration from a collagen matrix, as would be found in a periwound environment, into a neomatrix. Subsequently, 3 fibronectin (FN) functional domains were found to be necessary and sufficient for fibroblast movement. From this discovery, an intermolecular cross-linked hyaluronan (HA) decorated with the 3 FN domains was engineered and demonstrated to enhance fibroblast migration in vitro and in porcine cutaneous wound repair in vivo. Recently, 4 sites in 3 FN domains were found to bind platelet-derived growth factor-BB (PDGF-BB). PDGF-BB remained active while bound to these FN growth factor (GF)-binding domains or peptides. Importantly the ability of PDGF-BB to act as a survival factor for FN-deficient cells is dependent on FN GF-binding domains or peptides. Since burn wounds can be deficient in FN through thermal denaturation and enzymatic degradation, these findings raise the possibility that FN GF-binding domains or peptides may be useful in burn therapy. Here we propose to create a topical preparation for deep partial thickness burn wounds containing a FN growth factor-enhancing peptide (GFEP). To this end we propose to screen small (<15 amino acid) FN peptides for their ability to bind PDGF-BB and promote FN null fibroblast survival and proliferation (AIM 1), assay FN PDGF-binding peptides in conjunction with PDGF for their ability to promote activation, proliferation and migration of human fibroblasts and microvascular endothelial cells (AIM 2), and test FN PDGF-binding peptides in conjunction with PDGF for their capacity to limit injury, enhance healing and prevent scarring of burn wounds in a porcine model that has been previously validated (AIM 3). There are more than 1 million burns each year in the US, resulting in 700,000 emergency department visits, 45,000 hospital admissions, and 4,500 deaths. Methods aimed at preventing burn progression have been the focus of intense research but these results have been disappointing. Here we propose to create a topical preparation for deep partial thickness burn wounds containing a growth factor-enhancing peptide that was recently discovered at SUNY Stony Brook and has the remarkable ability to promote tissue cultured cell survival and proliferation.