Formation, renewal and repair of connective tissue is affected by the aging process. The key issues in this proposal are (1) to develop further and exploit a model of chronic wound healing in normal and aged rats; (2) to understand the relationship between aging, growth factor action, and wound repair, (3) to determine whether the accelerated aging syndrome, Hutchinson-Gilford progeria (HGP), reflects a defect in RNA catabolism that leads to overexpression of matrix components such as elastin and type IV collagen; (4) to examine the fibroblast phenotype and putative precursor levels as a function of age; and (5) to evaluate the wound healing consequences of genetic or immunologic interference in a variety of tissue repair models by describing expression dynamics, by evaluating the effects of growth factor addition, and by interfering in specific growth factor pathways. Of particular significance is the demonstration that gene therapy at the wound site is an effective cytokine delivery system with the ability to improve normal wound healing and to reverse biomechanical defects in the wounds of aging animals. The investigators have developed new, chronic wound (dermal ulcer) models that can now be used to test the hypothesis that conventional or gene therapy delivery of growth factors alone, in combination, or in sequence, can improve the rate and quality of repair in non-healing wounds. New antagonists and transgenic animals will be used to identify key elements in the wound healing sequence. The mechanistic basis for age-related healing deficiencies is uncertain. The investigators will test the hypotheses that apoptosis follows a different course in aging wounds and that wound remodeling is retarded. The issue of fibroblast progenitors in wound repair is unsettled. They will also evaluate the hypothesis that stem cells involved in repopulating wound tissue are less available as the organism ages. Regarding accelerated aging, elevated elastin mRNA and production is not correlated with increased elastin gene transcription, suggesting that elastin mRNA turnover is reduced in HGP fibroblasts. They will evaluate the stability of elastin and collagen IV mRNAs to determine whether a general defect in RNA catabolism is operative in HGP. These findings will be compared to matrix metabolism in normal skin fibroblasts from young and old individuals and from cells aged in vitro.
| 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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