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Project 3: Novel injury-regulated genes and their roles
in cutaneous wound repair
The results obtained with KGF and activin provided evidence
for a functional role of injury-regulated genes in the wound healing process.
To gain further insight into the molecular mechanisms that underlie the
repair process and to identify novel players in wound repair, we attempted
to identify systematically genes that are differentially expressed in
wounded compared with normal skin. We exclusively compared normal skin
with very early wounds, because only minor changes in the cellular composition
occur during this initial repair period.
Several interesting genes were identified which were shown
to play an important role in wound repair. Due to the usefulness of this
approach in identifying new players in wound repair, this screen was extended
in collaboration with Switch Biotech in Munich, Germany. A series of novel
wound-regulated genes were identified which encode enzymes, receptors,
cytokines, cytoskeletal proteins, transcription factors and novel proteins.
The roles of these genes in normal and impaired wound repair and in other
tissue repair processes is currently being characterized. In addition,
clinical collaborations have been initiated to study a possible role of
our new molecules in human skin disease.
Selected publications:
- Beer, H.-D., Vindevoghel, L., Gait, M.J., Revest, J,-M.,
Duan, D.R., Mason, I., Dickson, C., and Werner, 5 (2000). Fibroblast
growth factor (FGF) receptor 1–IIIb is a naturally occurring functional
receptor for FGFs which is preferentially expressed in the skin and
the brain. J Biol. Chem., in press.
- Brauchle, M., Madlener, M., Wagner, A.D., Angermeyer,
K., Lauer, U., Hofschneider, P.H., Gregor, M., and Werner, 5. (1996).
Keratinocyte growth factor is highly overexpressed in inflammatory bowel
disease. Am. J Pathol. 149, 521–529.
- Frank, S., Hübner, G., Breier, G., Longaker, M.T.,
Greenhalgh, D., and Werner, S. (1995). Regulation of vascular endothelial
growth factor expression in cultured keratinocytes: Implications for
normal and impaired wound healing. J Biol. Chem., 270,
12607–12613.
- Frank, S., Munz, B., and Werner, 5. (1997). The human
homologue of a bovine non-selenium glu-tathione peroxidase is a novel
keratinocyte growth factor-regulated gene. Oncogene 14,
915–921.
- Hübner, G., Hu, Q., Smola, H., and Werner, 5. (1996).
Strong induction of activin expression after injury suggests an important
role of activin in wound repair. Dev. Biol., 173, 490–498.
- Hübner, G., Brauchle, M., Gregor, M., and Werner, 5.
(1997). Activin A: A novel player and inflammatory marker in inflammatory
bowel disease? Lab. Invest, 77, 311–318.
- Munz, B., Frank, S., Hübner, G., Olsen, E., and Werner,
S. (1997a). A novel type of glutathione peroxidase: Expression and regulation
during wound repair. Biochem. J 326, 579–585.
- Munz, B., Smola, H., Engelhardt, F., BleueI, K., Brauchle,
M., Lein, I., Ewans, L.W., Huylebroeck, D., Balling, R., and Werner,
5. (1999). Overexpression of activin in the epidermis of transgenic
mice reveals new activities of activin in keratinocyte differentiation,
cutaneous fibrosis and wound repair. EMBOJ, 18, 5205–5215.
- Tretter, Y., Hertel, M., Munz, B., ten Bruggencate,
G., Werner, S. and Alzheimer, C. (2000). Induction of activin A is essential
for the neuroprotective action of bFGF in vivo. Nat. Med. In
press.
- Werner, S., Peters, K.G., Longaker, M.T., Fuller-Pace,
F., Banda, M., and Williams, L.T. (1992). Large induction of keratinocyte
growth factor expression in the dermis during wound healing. Proc.
Nat. Acad. Sci. USA, 89, 6896–6900.
- Werner, S., Smola, H., Liao, X., Longaker, M.T., Kneg,
T., Hofschneider, P.H., and Williams, L.T. (1994a). The role of KGF
in morphogenesis of epithelium and reepithelialization of wounds. Science,
266, 819–822.
- Werner, S. (1998). Keratinocyte growth factor: A unique
player in epithelial repair processes. Cytokine & Growth Factor
Rev. 9, 153–165.
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