Chronic non-healing wounds are a major health problem commonly found in the elderly population. Local tissue hypoxia, resulting from underlying health problems such as diabetes, venous stasis and peripheral vascular disease, is a common feature accompanying all types of chronic wounds in the clinical setting. The investigator's long-term goal is to develop methods for the prevention and treatment of chronic wounds in the elderly based on an understanding of pathobiological mechanisms of chronic wounds and the function of growth factors in coordinating wound healing in the chronic wound microenvironment. Preliminary studies have focused on developing an ischemic murine model to generate a hypoxic tissue environment for wound healing studies. Using this model and cell culture, the investigators have characterized ischemic modulation of TGF-b and matrix metalloproteinase expression in young animals and cells. Their overall hypothesis is that tissue hypoxia negatively impacts wound healing in aged systems, with specific impairment of the pro-healing effects of the growth factor TGF-b1. They further hypothesize this impairment occurs at the level of TGF-b1 expression and signal transduction that, in part, limits healing by affecting TGF-b1 control of type I collagen expression and matrix metalloproteinase (MMP) expression/ activity. Control of type I collagen expression and MMP activity is required for a normal healing process. This hypothesis will be tested using the ischemic flap wound in an aged murine model. This proposal presents experiments designed to elucidate the cellular and molecular mechanisms altered in aged systems that affect the normal role of TGF-b1 in wound healing.
Their specific aims are to (1) characterize the effect of ischemia on the wound healing of aged mouse wounds, and examine hypoxia-modulated alterations of TGF-b isoforms and TGF-b receptors in wound tissue and fluid; (2) examine expression of downstream effector genes of TGF-b1, specifically collagen and collagen-degrading matrix metalloproteinases (MMPs), in aged mouse ischemic wounds; (3) investigate the molecular and cellular basis for hypoxia-impaired wound healing in aged mice by extending in vivo observations to primary cultures of aged murine dermal fibroblasts to examine hypoxic modulation of early TGF-b signal transduction; (4) to investigate the hypoxia modulation of collagen and matrix metalloproteinase expression in aged murine dermal fibroblasts and the potential role of TGF-b1 in mediating these changes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Medicine
United States
Zip Code
Liu, W Robert; Lu, Leonard; Rosenberg, David S et al. (2007) Synergistic activation of extracellular signal-regulated kinase in human dermal fibroblasts by human telomerase reverse transcriptase and transforming growth factor-beta1. J Surg Res 143:415-21
Sisco, Mark; Liu, W Robert; Kryger, Zol B et al. (2007) Reduced up-regulation of cytoprotective genes in rat cutaneous tissue during the second cycle of ischemia-reperfusion. Wound Repair Regen 15:203-12
Mogford, Jon E; Liu, W Robert; Reid, Russell et al. (2006) Adenoviral human telomerase reverse transcriptase dramatically improves ischemic wound healing without detrimental immune response in an aged rabbit model. Hum Gene Ther 17:651-60
Bengali, Zain; Pannier, Angela K; Segura, Tatiana et al. (2005) Gene delivery through cell culture substrate adsorbed DNA complexes. Biotechnol Bioeng 90:290-302
Gurjala, Anandev N; Liu, W Robert; Mogford, Jon E et al. (2005) Age-dependent response of primary human dermal fibroblasts to oxidative stress: cell survival, pro-survival kinases, and entrance into cellular senescence. Wound Repair Regen 13:565-75
Mogford, Jon E; Sisco, Mark; Bonomo, Steve R et al. (2004) Impact of aging on gene expression in a rat model of ischemic cutaneous wound healing. J Surg Res 118:190-6
Mogford, Jon E; Roy, Nakshatra K; Cross, Kevin J et al. (2003) Use of hypoxia-inducible factor signal transduction pathway to measure O2 levels and modulate growth factor pathways. Wound Repair Regen 11:496-503
Xia, Y P; Zhao, Y; Tyrone, J W et al. (2001) Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: implication for chronic wounds in the elderly. J Invest Dermatol 116:50-6
Wu, L; Xia, Y P; Roth, S I et al. (1999) Transforming growth factor-beta1 fails to stimulate wound healing and impairs its signal transduction in an aged ischemic ulcer model: importance of oxygen and age. Am J Pathol 154:301-9
Abbott, R E; Corral, C J; MacIvor, D M et al. (1998) Augmented inflammatory responses and altered wound healing in cathepsin G-deficient mice. Arch Surg 133:1002-6

Showing the most recent 10 out of 12 publications