Wound healing is delayed and impaired during aging, and multiple mechanisms converge to alter repair. Previous and continuing work has shown that growth factors and their genes can be used to accelerate the repair process. To improve the capacity to screen for vulnerary agents, we add a novel model, the bioluminescent mouse, in which luciferase reporter genes, driven by specific murine promoters such as collagen (COL1A2) and collagenase (MMP-13), emit photons from the site of repair that localize and quantify gene expression. The MMP-13 model will be further refined by defining upstream regulatory elements. New transgenic strains to identify a marker of aging skin and wounds, MMP-2, will be developed. Together with conventional wound healing models, these transgenic systems will allow kinetic, real-time analysis of the mechanism of activity of therapeutic genes in a noninvasive mode. Fibroblast growth factor delivered by gene gun and adenoviral vectors, will be used to observe the effects of a growth factor on specific matrix genes. Since the lag in wound healing can be primed by re-excision, we hypothesize that the age-related delay in repair is due to depletion of stem cells that may be derived from local or circulating sources. Fibroblast and angiogenic precursor cells will be traced in adoptive bone marrow transfer expenments using selective, bioluminescent or biochemical, transgenic markers of each lineage (collagen l/MMP-13; flk-1). Gene therapy is a promising strategy for treating problem wounds, and it is a powerful method for discovering molecules active in the process. Activin cDNA shows vulnerary activity. Genes for activin and its antagonist, follistatin, will be validated in conventional and transgenic models of wound repair using biolistic and adenoviral delivery systems. This pair of genes will act as a prototype for the application of gene therapy and transgenic, reporter animals to functional genomics. The extracellular matrix is altered in aging, including the accumulation of crosslinks due to nonenzymatic glycation. A novel breaker of advanced glycation endproduct crosslinking, will be tested for its ability to alter the biomechanical properties of skin and the rate of wound repair in an established rat model.
| Davidson, Jeffrey M; Yu, Fang; Opalenik, Susan R (2013) Splinting Strategies to Overcome Confounding Wound Contraction in Experimental Animal Models. Adv Wound Care (New Rochelle) 2:142-148 |
| Hines, Kelly M; Ashfaq, Samir; Davidson, Jeffrey M et al. (2013) Biomolecular signatures of diabetic wound healing by structural mass spectrometry. Anal Chem 85:3651-9 |
| Adolph, Elizabeth J; Hafeman, Andrea E; Davidson, Jeffrey M et al. (2012) Injectable polyurethane composite scaffolds delay wound contraction and support cellular infiltration and remodeling in rat excisional wounds. J Biomed Mater Res A 100:450-61 |
| Makowski, Alexander J; Davidson, Jeffrey M; Mahadevan-Jansen, Anita et al. (2012) In vivo analysis of laser preconditioning in incisional wound healing of wild-type and HSP70 knockout mice with Raman spectroscopy. Lasers Surg Med 44:233-44 |
| Hafeman, Andrea E; Zienkiewicz, Katarzyna J; Zachman, Angela L et al. (2011) Characterization of the degradation mechanisms of lysine-derived aliphatic poly(ester urethane) scaffolds. Biomaterials 32:419-29 |
| Schultz, Gregory S; Davidson, Jeffrey M; Kirsner, Robert S et al. (2011) Dynamic reciprocity in the wound microenvironment. Wound Repair Regen 19:134-48 |
| Hoffmann, Daniel C; Textoris, Christine; Oehme, Felix et al. (2011) Pivotal role for alpha1-antichymotrypsin in skin repair. J Biol Chem 286:28889-901 |
| Saraswati, Sarika; Alfaro, Maria P; Thorne, Curtis A et al. (2010) Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS One 5:e15521 |
| Martinez-Ferrer, Magaly; Afshar-Sherif, Ali-Reza; Uwamariya, Consolate et al. (2010) Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure. Am J Pathol 176:98-107 |
| Davidson, Jeffrey M (2010) Can scarring be turned off? Am J Pathol 176:1588-91 |
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