Poor wound healing in compromised post surgical or chronic wound patients, represents a major national health problem. Most patients' wound healing problems result from wound tissue hypoxia. The long term objective of this proposal is to develop further understanding through animal models and in vitro studies, of how growth factors initiate and sustain the events of successful healing, particularly in the setting of ischemic tissue hypoxia. This knowledge would be used to develop effective treatment of patients with poor wound healing. The ischemic dermal ulcer model which demonstrates impaired healing, will be quantifiably evaluated for wound healing rate and quality. The role of growth factor treatment in the setting of impaired healing due to ischemia will be studied. The processes of epithelialization, granulation tissue formation, and angiogenesis will be quantified using histologic analysis, immunohistochemistry, and vascular perfusion studies. Changes in gene expression will be studied by quantitative polymerase chain reaction analysis, focusing on the FGF and TGF-B families and their receptors. Hyperbaric oxygen therapy will be studied as an adjuvant treatment in the management of impaired healing, and as a possible regulator of growth factor mediated gene expression. The effects of HBO on GM-CSF and M-CSF treatment of ischemic wounds will be examined to see if the synergistic effects of growth factors and HBO are a general phenomena. In vitro studies of the cellular response to hypoxia will allow examination of the individual component cells involved in wound healing, including fibroblasts, endothelial cells and macrophages. The role of growth factor function in the setting of variable oxygen levels will be studied. A mechanistic basis for the synergy between growth factor and intermittent hyperoxia will be pursued. Cell proliferation and gene expression as analyzed by PCR in human and rabbit cells will be measured in response to key growth factors and hypoxia.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041303-08
Application #
2180797
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1991-07-01
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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

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