Fas (CD95, APO-1) is a cell surface receptor of the tumor necrosis factor family expressed on most rapidly dividing and self-renewing cells, including lymphocytes, hepatocytes, epithelial cells, and a wide variety of tumor cells. Fas is widely known as a """"""""death receptor"""""""" and can induce programmed cell death when engaged by Fas Ligand (FasL, CD95L) or anti-Fas antibodies. Paradoxically, Fas engagement can also result in accelerated proliferation of T lymphocytes and some tumor cells. The stimulatory function of Fas as a receptor has received little attention to date. We have found that cell surface Fas expression is upregulated in response to increasing glucose concentrations in vitro, in transformed cell lines and in freshly isolated cells from a variety of tissue origins. It is well established that glucose supplementation enhances cell proliferation in vitro, and topical glucose application accelerates wound healing in vivo. The mechanism by which this phenomenon occurs remains poorly understood. We propose that the documented increase in glucose utilization which accompanies wound healing mediates upregulated Fas expression, and that Fas engagement enhances the rate of cell proliferation during wound healing and tissue regeneration. The following specific aims will be used to test this hypothesis: 1. To determine if glucose metabolism is involved in the regulation of Fas expression and susceptibility to Fas-induced ceath. 2. To determine if Fas is involved in wound healing, and if the acceleration of wound healing by exogenous glucose application is mediated through Fas. 3. To determine if endogenous Fas expression, and exogenous Fas engagement by anti-Fas antibodies or FasL accelerates wound healing. The experiments proposed here will reveal the physiological role of Fas in tissue repair, and may lead to the therapeutic use of Fas and FasL in the treatment of non-healing wounds and to accelerate tissue regeneration in vivo and in vitro in bioengineered matrices.
| Harper, Mary-Ellen; Antoniou, Andreas; Villalobos-Menuey, Elizabeth et al. (2002) Characterization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 16:1550-7 |
| Desbarats, J; Newell, M K (2000) Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6:920-3 |
