The Metabolic Basis of Wound Healing:
Our aim i s to determine the mechanisms by which the phenotypes and functions of wound cells are determined by the extreme local environment which results from injury. The strategy is aimed at the metabolic features of wounds that elicit growth factors, stress proteins, and regulate angiogenesis and collagen synthesis. There are 5 sections; a Core and 4 projects which are as follows: Part I: Hypothesis: the hypoxic, heavily lactated, highly oxidative conditions in wounds lead to a reduction in the NAD+ pool and a subsequent loss of ADPRibosylations that mediate collagen and VEGF gene expression, protein production, and post translational modification. The effects of IGF-1 and some other growth factors are also mediated through this mechanism. Part 2: Hypothesis: oxidants produced largely by leukocytes play an essential role in wound healing by stimulating VEGF production and collagen gene expression via redox signaling. Part 3: Hypothesis: (a) """"""""Stress proteins"""""""" represent a spectrum of phenotypic changes that are important to healing; (b) enhancement of collagen and VEGF gene expressions are only a small portion of the reparative phenotype and that oxidants and hypoxia will instigate hox genes in the course of instigating healing. In part 4, we proceed from our find that hypoxia is inimicable to angiogenesis, collagen processing, and immunity. We now hypothesize that a) the prognosis for healing in both acute and chronic and chronic wounds can be calculated from oxygen measurements, b) that cycled iatrogenic enhancement of tissue P02 stimulates angiogenesis, and c) that antibiotic resistant organisms are susceptible to oxidative leukocytic killing. Lastly, we propose to refine our knowledge of control of oxygen transport to wounds on complex flap model. Significance: Clinical advantages have accrued through our past mechanistic research. We expect to gain insights into treatment of both chronic and acute wounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM027345-24
Application #
6693394
Study Section
Special Emphasis Panel (ZGM1-TB-6 (01))
Program Officer
Somers, Scott D
Project Start
1980-01-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2005-12-31
Support Year
24
Fiscal Year
2004
Total Cost
$1,094,026
Indirect Cost
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Hunt, Thomas K; Aslam, Rummana S; Beckert, Stefan et al. (2007) Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal 9:1115-24
Hansen, Scott L; Dosanjh, Amarjit; Young, David M et al. (2006) Hemangiomas and homeobox gene expression. J Craniofac Surg 17:767-71
Rosen, Noah A; Hopf, Harriet W; Hunt, Thomas K (2006) Perflubron emulsion increases subcutaneous tissue oxygen tension in rats. Wound Repair Regen 14:55-60
Hopf, Harriet W; Gibson, Jeffrey J; Angeles, Adam P et al. (2005) Hyperoxia and angiogenesis. Wound Repair Regen 13:558-64
Fries, Richard B; Wallace, William A; Roy, Sashwati et al. (2005) Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat Res 579:172-81
Hansen, Scott L; Myers, Connie A; Charboneau, Aubri et al. (2003) HoxD3 accelerates wound healing in diabetic mice. Am J Pathol 163:2421-31
Hansen, Scott L; Young, David M; Boudreau, Nancy J (2003) HoxD3 expression and collagen synthesis in diabetic fibroblasts. Wound Repair Regen 11:474-80
Trabold, Odilo; Wagner, Silvia; Wicke, Corinna et al. (2003) Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen 11:504-9

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