Master of Science
Turley, Eva A
Systemic sclerosis is a chronic, fibrotic disorder associated with high disease-specific mortality and morbidity. Cutaneous manifestations include dermal thickening and obliteration of dermal adipose tissue. The efficacy of function-blocking Rhamm peptides, NPI-110 and NPI-106, were tested in reducing skin fibrosis and promoting adipogenesis in a bleomycin-induced mouse model of systemic sclerosis. NPI-110 reduced both visible measures of fibrosis (dermal thickness, collagen density, and fibril bundling) and mRNA expression of pro-fibrotic genes (Tgfb1, c-Myc, Col1a1, Col3a1). While there was no measurable change in dermal adipose thickness, NPI-110 treatment upregulated Perilipin mRNA and Adiponectin protein expression and is therefore hypothesized to create a pro-adipogenic microenvironment. NPI-106 was less effective in reversing dermal fibrosis and did not affect adipogenesis. Transcriptomic analyses suggest a mechanism where Rhamm stabilizes β-catenin, activates Erk1 and c-Myc, and causes fibroblast activation and suppression of adipocyte differentiation. Rhamm function-blocking peptides reverse these effects and present a novel treatment method for cutaneous fibrosis in systemic sclerosis.
Wu, Kitty Y., "The Effect of Function-blocking RHAMM Peptides in a Mouse Model of Bleomycin-induced Systemic Sclerosis" (2018). Electronic Thesis and Dissertation Repository. 5884.