Myofibroblasts are a unique class of cells critical in normal human organogenesis and wound repair. Dysregulation of the normal mechanisms of myofibroblast apoptosis are proposed to play a role in the development of fibroproliferative diseases such as idiopathic pulmonary fibrosis. Therefore the goals of this proposal are to (i) identify the mechanisms that allow myofibroblasts to be eliminated at the completion of normal wound repair and (ii) uncover the mechanisms by which a specific survival pathway involving Akt/protein kinase B protects myofibroblasts from apoptosis. Based upon data from our laboratory and others, we hypothesize that (i) death receptor activation with its resultant caspase-8 and effector caspase activation is necessary for growth factor withdrawal-induced apoptosis and that (ii) the p53 tumor suppressor gene modulates the apoptotic signal through its effects on death receptor expression and trafficking, death ligand expression and the Bcl-2 family of proteins. In addition, we propose that (iii) Akt mediates its prosurvival effects through as-of-yet unidentified mechanisms, potentially including: (i) death receptor phosphorylation, (ii) death receptor localization, (iii) FADD phosphorylation and (iv) inhibition of p53- dependent transcription. These hypotheses will be tested in a growth factor withdrawal model of apoptosis in the CCL39 myofibro blast cell line and in primary cultured myofibroblasts of murine origin. Ultimately, the techniques, strategies and results of these studies can be applied to a range of fibroproliferative diseases and serve as a basis for developing novel pharmacological targets for new therapies for fibrotic lung disease.
Frankel, Stephen K; Moats-Staats, Billie M; Cool, Carlyne D et al. (2005) Human insulin-like growth factor-IA expression in transgenic mice promotes adenomatous hyperplasia but not pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 288:L805-12 |
Van Linden, Annemie A; Cottin, Vincent; Frankel, Stephen K et al. (2005) Hierarchical phosphorylation of the TNF-alpha receptor, TNF-R1, by p42Mapk/Erk at basic Pro-directed kinase sites. Biochemistry 44:6980-9 |
Wynes, Murry W; Frankel, Stephen K; Riches, David W H (2004) IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J Leukoc Biol 76:1019-27 |