(Taken from the application): Following skin injury, fibroblasts enter the wound, proliferate, and produce and reorganize connective tissue, restoring strength and function to the wounded site. If this process is disordered or excessive, fibrotic scarring results. Keloids and hypertrophic scars are painful and disfiguring examples. In scleroderma, fibrotic scarring forms in skin and other organs without prior injury, causing deformity, debilitation, and in some cases, death. The long-term goal to which the proposed research is directed is to understand how excessive fibrosis occurs and to develop new ways to prevent or treat it. Fibroblasts isolated from fibrotic tissues have many distinctive features, but it remains unclear how they acquire these features and whether all fibroblasts are equally involved. Prior investigations have defined heterogeneous features of normal rodent fibroblast subsets based on whether they express the cell surface marker Thy-l. However, to date Thy-l expression in fibrotic states has not been explored, nor has there been correlation of expression of CD90, the human Thy-l equivalent, with human 'fibroblast heterogeneity. We hypothesize that absence of Thy-1CD90 on the fibroblast surface correlates with a phenotype predisposed to participate in fibrotic responses, and that examination of fibrogenic lesions in human skin will demonstrate a higher proportion of fibroblasts lacking CD90 compared to normal skin. Thus, the aims of the project are: 1) to characterize fibroblast CD90 expression in hypertrophic scars. keloids, and scleroderma-affected skin in comparison to normal skin and normal scars, by immunostaining of tissue sections and cultured fibroblasts; 2) to characterize expression of type I collagen and connective tissue growth factor in sorted CD90 (-/+) and Thy-l (-/+) fibroblast populations: and to define the profile of differential gene expression in CD90 and Thv-l(-/+) subpopulations. Establishing the role of fibroblast Thy-1/CD90 expression in human fibrogenic skin diseases is likely to unlock mechanisms of fibroblast activation and lead to more effective treatments for fibrotic disorders in skin and other tissues.
| Barker, Thomas H; Pallero, Manuel A; MacEwen, Mark W et al. (2004) Thrombospondin-1-induced focal adhesion disassembly in fibroblasts requires Thy-1 surface expression, lipid raft integrity, and Src activation. J Biol Chem 279:23510-6 |
| Barker, Thomas H; Grenett, Hernan E; MacEwen, Mark W et al. (2004) Thy-1 regulates fibroblast focal adhesions, cytoskeletal organization and migration through modulation of p190 RhoGAP and Rho GTPase activity. Exp Cell Res 295:488-96 |
| Hagood, James S; Mangalwadi, Anandit; Guo, Benliu et al. (2002) Concordant and discordant interleukin-1-mediated signaling in lung fibroblast thy-1 subpopulations. Am J Respir Cell Mol Biol 26:702-8 |
