The long term objectives are to understand the regulation and function of wound insulin-like growth factor-I (IGF-1) and IGF binding protein (IGFBP) levels during tissue repair, and also to use this knowledge to modulate tissue repair in disease states. In this project, our knowledge of IGF-I will be expanded by in vivo and in vitro studies. Experiments will be initiated to understand the mechanisms of IGF-I actions in wounds and how IGF-I may be involved in pathological states of repair and trauma.
In Aim 1 human fibroblasts will be used to investigate whether IGF_1 phosphorylates nuclear poly(ADP-ribose) (PADPR) synthetase thereby inhibiting its activity and stimulating collagen gene expression. Whether the inhibitory effect of IGF-I on PADPR synthetase increases the cellular level of cyclic ADP-ribose will be examined in Aim 2. Cyclic ADP-ribose induces the release of intracellular calcium and could explain this same effect of IGF-I. Investigations into the role of IGF-I in glucocorticoid impaired wounds will be pursued to learn more about the interrelation of lactate, TGFb, vitamin A and inflammation in tissue repair. The second part of this grant deals with the actions and levels of IGF-I, IGFBPs, and IGFBP proteases in normal and pathologic wounds.
Aim 4 will examine whether the IGF-I gene is over-expressed or IGFBPs are decreased in wounds characterized by increased collagen synthesis, hypertrophic scars and keloids. IGF-I and IGFBP-3 will be assayed by immunohistochemical techniques.
Aim 5 will investigate in a rat model the role of IGF-I and IGFBPs in the formation of abdominal adhesions. The ultimate goal of Aims 4 and 5, if IGF-I were shown to have a pathological role, would be to block its action by an inhibitory IGFBP. The ability of IGFBP-3 to inhibit increased IGF-I activity and modulate tissue repair will be investigated in both Aims 4 and 5. In patients with trauma, head injury and burns the plasma IGF-I, IGFBPs, and IGFBP proteases will be determined in order to establish the relationship of abnormal levels to several parameters including the catabolic state, wound healing, infection, hospital stay and recovery.
| Gimbel, Michael L; Rollins, Mark D; Fukaya, Eri et al. (2009) Monitoring partial and full venous outflow compromise in a rabbit skin flap model. Plast Reconstr Surg 124:796-803 |
| Ogino, Tetsuya; Than, Tin Aung; Hosako, Mutsumi et al. (2009) Taurine chloramine: a possible oxidant reservoir. Adv Exp Med Biol 643:451-61 |
| 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; 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 |
| Boudreau, Nancy; Myers, Connie (2003) Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment. Breast Cancer Res 5:140-6 |
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