Interstitial fibrosis is the final common pathway to most forms of end-stage renal disease. Fibroblasts are the principal agent responsible for this fibrotic process but little is known about their origin or how they are engaged during renal injury. Part of the problem has been that good reagents for identifying fibroblasts in normal tissues have not been not available. Over the last few years these investigators tried to develop new probes to help better identify these cells. To facilitate the study of fibroblasts, they recently cloned a protein called fibroblast-specific protein-1 (FSP1) which is exquisitely specific for fibroblasts in murine tissues. FSP1 belongs to the calmodulin-S100-troponin C superfamily of intracellular calcium-binging proteins. Members of the S100 superfamily have a discrete role in microtubule dynamics, cytoskeletal-membrane interactions, cellular growth, and differentiation. FSP1 is not only a marker of fibroblasts, but also plays an instructive role in shaping their mesenchymal phenotype as indicated by the fact that overexpression of FSP1 in tubular epithelium induces a phenotypic conversion to fibroblasts, induction of FSP1 expression in tubular epithelium by cytokines produces the same change, and this phenotypic conversion can be blocked by antisense oligomers to mRNA encoding FSP1. This protein also appears to have a similar role in vivo, as tubular epithelium trapped by interstitial nephritis begin expressing FSP1 while the disaggregate from the nephron during the early stages of fibrosis. As tubular atrophy sets in, the number of FSP1+ cells increase, suggesting that fibroblasts might arise locally through a process of epithelial-mesenchymal transformation (EMT). The applicant's intend to further evaluate this EMT hypothesis with transgenic and molecular technology using FSP1 as a probe. For example, a yeast one-hybrid system has been set up to screen for transcription factors that bind to a fibroblast-specific site (FTS-1) that was found in the FSP1 promoter that confers fibroblast specificity. A FSP1 knockout mouse will explore the role of FSP1 in the development and fate of fibroblasts, other mice will have their tubular epithelium marked with a dormant transgene (LacZ) that can be activated with Cre-recombinase to see if it later appears in fibroblasts during fibrogenesis, and finally, they have developed a molecular suicide approach using thymidine kinase transgenes with gancyclovir to attenuate renal fibrosis by selectively killing tissue fibroblasts. Identification of upstream regulators of transcription and a better understanding of FSP1 in gene-modified mice is a first step in trying to uncover the molecular program that guides the mesenchymal phenotype of fibroblasts. It may be a key to understanding how to control their behavior during disease.
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