Recent observations in our laboratory have implicated the Fas/FasL system as a key mediator of apoptosis following injury by UV-B and gamma irradiation, as well as heat shock. Because Fas/FasL interactions are critical to the control of autoimmnuity, as illustrated by the lpr and gld mutant mouse strains, we hypotheisze that autoimmune disease may depend on effective Fas regulation and the efficient induction of apoptosis in injured cells. In this proposal, we will study the biology of Fas upregulation after injury using normal cells, with particular emphasis on the role of the p53 molecule. We are particularly interested in p53's role in autoimmunity because of our striking preliminary data that mice deficient in p53 develop higher-titer auto-antibodies. We hypothesize that p53 may act via Fas to induce apoptosis of injured cells, and that the p53-/-mice may be unable to eliminate such cells and may retain potentially autoimmunogenic cells. We will define the cells responsible for induction of autoimmunity in p53-/- mice. We will test the role of both Fas and p53 in mediating local pathology and in systemic autoimmune disease by exposing normal and mutant mice to ionizing and UV-B radiation. Finally, we will extend our preliminary data using Fas-binding M13 bacteriophage clones to develop reagents to modify Fas-mediated apoptosis, both as agonists and antagonists. We will synthesize agonistic and antagonistic Fas-binding peptides based on sequences of Fas-binding phages we have identified from a phage display library, and will assess their ability to induce and to block cell death in vivo and in vitro. Overall, the proposed studies should help clarify the role of Fas in immune injury and systemic autoimmune disease, and its participation as a sentinel molecule which responds to environmental stress.
| Kuan, Anita P; Cohen, Philip L (2005) p53 is required for spontaneous autoantibody production in B6/lpr lupus mice. Eur J Immunol 35:1653-60 |
| Cohen, Philip L; Caricchio, Roberto (2004) Genetic models for the clearance of apoptotic cells. Rheum Dis Clin North Am 30:473-86, viii |
| Caricchio, Roberto; McPhie, Lenese; Cohen, Philip L (2003) Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 171:5778-86 |
| Caricchio, R; D'Adamio, L; Cohen, P L (2002) Fas, ceramide and serum withdrawal induce apoptosis via a common pathway in a type II Jurkat cell line. Cell Death Differ 9:574-80 |
