Aging, growth and development bring about progressive changes in the capacity to repair and regenerate. The greatest economic costs come at the end of life as increasingly fragile skin and immobility conspire with ischemia and a delayed healing response to generate chronic wounds. This proposal combines efforts to understand age-related aspects of the regenerative and healing responses in four specific aims. First, the relative importance of the mesenchymal stem cell (MSC) in wound healing will be tested by adoptive transfer of marrow and by local administration of MSCs exchanged between young and old mice. Mouse strains with different regenerative capacities will also be compared. The next three aims relate to the role of the Wnt signal pathway.
The second aim extends from preliminary observations of the enhanced regeneration of wounds in mice that contain a conditional FSP-cre/R.-cateninAex3 allele for stabilized li-catenin, the major mediator of canonical Wnt signaling. This regenerative phenotype will be studied in different types of wound models, and we will determine if MSCs from conditional expressors of stabilized R-catenin differ in their capacity to promote healing and regeneration. We will compare the capacity of stabilized li-catenin, MRL/""""""""super-healer"""""""", and wild type mouse MSCs to modify the healing process by adding stem cells to the wound site.
Aim three focuses on the role the Wnt pathway in MSC biology. We will determine if Wnt signaling is critical to the properties of the MRL.
The fourth aim concentrates on the biological properties of FGF binding protein (FGF-BP). In impaired wounds, FGF-BP produces a remarkable expansion of granulation tissue, suggesting that availability of FGF is limited in chronic wound states such as ischemia. Since FGF-BP is reportely a direct target of IS-catenin, we will also examine FGF-BP expression in wounds of the MRL and stabilized li-catenin mouse. Normal and ischemic wounds from young and old rats will be compared for responses to FGF-BP supplementation by adenoviral gene transfer. The activity of FGF-BP will also be evaluated in vivo. These novel signal pathways may be able to convert the chronic wound into a normal wound as well as shift the equilibrium from repair to regeneration. Lay Summary: Tissue regeneration and repair progressively decline with age. We will study how stem cells that come from the bone marrow respond to signals that can improves the speed and quality of healing.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Williams, John
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Vanderbilt University Medical Center
Schools of Medicine
United States
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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
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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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