Systemic sclerosis (SSc) is a systemic disease characterized by excessive extracellular matrix synthesis and fibrosis of the skin and internal organs. Our work has focused on studying skin fibroblasts and understanding the-basis for their activation. However, only a small subset of fibroblasts appears to be activated in SSc, leading us to develop a hypothesis of clonal selection. Normal fibroblasts are heterogeneous for collagen synthesis, proliferation rate, response to cytokines and many other features, and factors like immune mediators and hypoxia during SSc pathogenesis may promote preferential overgrowth and activation of one or more clones. Apoptosis resistance of some clones can also play a role in such selection, and we have shown that SSc fibroblasts are more resistant to anti-Fas induced apoptosis compared to normal fibroblasts. Prolonged treatment of normal fibroblasts with TGF-beta1 also resulted in apoptosis resistance and increased proportion of myofibiroblasts. In this project, I propose to examine the basis for apoptosis resistance in SSc and TGF-beta1 treated fibroblasts. I will examine the relationship between myofibroblasts, apoptosis resistance and collagen synthesis in fibroblast clones, and whether they will be coordinately induced by TGF-beta1 in the same clone. will also test a hypothesis that myofibroblasts are an apoptosis resistant subpopulation of SSc fibroblasts and whether myofibroblasts are the subset of fibroblasts with high collagen synthesis. These results should help us understand how clonal selection and activation may occur in SSc fibroblasts, and what role TGF-beta1 may play in the pathogenesis of SSc.
Showing the most recent 10 out of 178 publications
