Impaired wound healing is a major problem for many surgical and burn patients but the causes of the healing abnormalities are not known. The hypothesis that topical growth factors can at least partially reverse the abnormalities of impaired healing has been proven. Previous works have focused on stimulating healing in two models of impaired healing, genetically diabetic C57BL/KsJ-db/db mice and in a similar malnutrition model. The obese, diabetic animals have insulin-resistant diabetes and significantly impaired healing. Unlike other rodent models, the majority of their healing results from granulation tissue formation and re- epithelialization, not contraction. Individual application of several growth factors (PDGF, bFGF, IGF-1, IGF-II or TGF-a) significantly augment healing in these animals. Growth factors were also found to reverse the healing deficit in malnourished animals. Since multiple growth factors with differing functions are active during healing, growth factor combinations should enhance healing to a greater extent than one. Preliminary work has proven that growth factor combinations do have synergistic effects on tissue repair.
The first aim will be to continue to examine the role of growth factors combinations in reversing healing abnormalities in clinically relevant impaired healing models. The specific growth factors to be examined will be the """"""""competence"""""""" factor PDGF, the """"""""progression"""""""" factor IGF-II and the keratinocyte mitogen TGF-alpha. The focus of the second aim will be to delineate at least some of the causes of healing impairments. The hypothesis directing the second aim is that healing abnormalities are related to impaired interactions with growth factors. In the sound, growth factor synthesis may be decreased, growth factor degradation may be increased or the cellular response to growth factors may be an impaired. Comparisons of healing between wounds that heal normally and those are impaired will be performed. Histology and immunohistochemistry will be used to compare cellular entry and differences in collagen deposition. Studies will continue with identifying the amounts of PDGF, IGF-II, TGF-alpha and TGF-beta. Interactions with growth factor receptors will be designed to identify which receptors are responsible for specific growth factor activities. Initial studies will try to identify which of the IGF receptors is responsible for IGF activity in wound healing.
The aim will be to learn how impaired healing responds to growth factors. The same techniques as for the second aim will be used except that changes in cellularity, collagen deposition, growth factor and receptor interactions will be examined after growth factor application. The ultimate goal is to use this knowledge to treat clinical healing problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050959-05
Application #
2698709
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Cho, Kiho; Adamson, Lee K; Park, Jaehak et al. (2003) Burn injury-mediated alterations in cell cycle progression in lymphoid organs of mice. Shock 19:138-43
Cho, Kiho; Adamson, Lee K; Hobson, Kristina G et al. (2002) Direct quantification of autologous serum albumin leakage after burn injury in mice. Burns 28:53-6
Cho, Kiho; Adamson, Lee; Park, Jae-Hak et al. (2002) Identification of truncated form of mouse HAX-1s gene (HAX-1xs) and characterization of its expression in small intestine and thymus of mice after burn injury. Shock 18:223-9
Cho, Kiho; Adamson, Lee K; Greenhalgh, David G (2002) Induction of murine AIDS virus-related sequences after burn injury. J Surg Res 104:53-62
Cho, K; Adamson, L K; Greenhalgh, D G (2001) Parallel self-induction of TNF-alpha and apoptosis in the thymus of mice after burn injury. J Surg Res 98:9-15
Kane, C D; Greenhalgh, D G (2000) Expression and localization of p53 and bcl-2 in healing wounds in diabetic and nondiabetic mice. Wound Repair Regen 8:45-58
Crowe, M J; Doetschman, T; Greenhalgh, D G (2000) Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol 115:11-Mar
Cho, K; Zipkin, R I; Adamson, L K et al. (2000) Differential regulation of c-jun expression in liver and lung of mice after thermal injury. Shock 14:182-6
McMurtry, A L; Cho, K; Young, L J et al. (1999) Expression of HSP70 in healing wounds of diabetic and nondiabetic mice. J Surg Res 86:36-41
Brown, D L; Kane, C D; Chernausek, S D et al. (1997) Differential expression and localization of insulin-like growth factors I and II in cutaneous wounds of diabetic and nondiabetic mice. Am J Pathol 151:715-24

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