Aging processes in human skin reflect to some degree afteration of the communication between cells of this complex tissue and their extracellular matrices. This project examines the mechanisms of matrix adhesion of human papillary and reticular dermal fibroblasts mediated by collagen and fibronectin(FN), as well as afteration of these mechanisms upon in vitro aging. Aging-related afterations in these adhesion mechanisms have now been identified. Both integrin and heparan sulfate proteoglycan binding activities of FN are required for many cell responses; the two aging processes generate shifts in cell dependence upon these two """"""""receptor"""""""" activities. Cycloheximide pretreatment of cells has also revealed deficiences of collagen-specific, but not FN-specific, receptors for F-actin stress fiber reorganization in aging cells; cells from Down's syndrome patients, a genetic model of premature aging, share this aging-related deficiency in adhesion responses. Molecular biological analyses of FN pre-mRNA splicing in these cells (using a novel double-primer extension assay) have also identified changes in the splicing pattern in the complex IIICS region of the FN transcript which harbors a unique cell-binding domain and which is aging-related. We will continue to test the hypothesis that matrix changes occur in human dermis as a consequence of aging processes and that these changes after dermal fibroblast responses at several levels of regulation.
Three specific aims will be pursued in our analyses. (a) We will identify the matrix adhesion receptors that become deficient in aging dermal fibroblasts from several normal individuals and from patients suffering from premature aging (Down's, Werner's, and progeria). The mechanisms of receptor deficiency will be described in clonal and mixed populations. (b) Transcriptional regulation of collagen- and FN-specific integrin genes will be analyzed during aging, as well as their clonal variabilfty within aging populations. (c) We will determine whether receptor deficiency in aging cells down-regulates expression of genes which are stringently dependent upon the matrix to which cells are anchored. These studies will provide further insight into the two-way communication(s) that occurs in the human dermis between papillary and reticular fibroblasts and their surrounding matrices, regulation of these communication processes, and their alteration upon aging in vivo or in vitro.
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| Flickinger, K S; Carter, W G; Culp, L A (1992) Deficiency in integrin-mediated transmembrane signaling and microfilament stress fiber formation by aging dermal fibroblasts from normal and Down's syndrome patients. Exp Cell Res 203:466-75 |
