Forced Activation of Wnt Signaling in Dermal Fibroblasts: A Genetic Model for Scleroderma

Radhika P. Atit, PhD
Case Western Reserve University

Project Summary:

The variation or changes in gene expression in the dermal fibroblasts leading to fibrosis and vascular defects in the skin and other tissues are unknown.  The Atit lab is using their new mouse model to test the hypothesis that activation of Wnt (a complex network of proteins responsible for multiple physiological processes) /beta-catenin signaling in dermal fibroblasts is sufficient for dermal fibrosis in adult skin. They have activated the canonical Wnt/beta-catenin pathway in skin and dermal fibroblasts during mouse embryonic development and analyzed the effects in embryonic and adult skin. The mouse skin has thickened dermis and avascular fibrotic lesions, which are hallmarks of cutaneous scleroderma in humans. Dr. Atit has proposed to: (1) characterize the mechanism underlying the dermal thickening and fibrosis in the mouse mutant; (2) determine the mechanism that results in the lack of blood vessels in the fibrotic regions; and (3) determine if the mouse mutant skin shares important molecular alterations with human scleroderma skin. The results of these studies will determine if this mouse mutant can be used as an in vivo model to study human cutaneous scleroderma and if Wnt/beta-catenin signaling should be considered as a new therapeutic target for the reduction of dermal fibrosis in scleroderma.

Research Update:

In scleroderma-affected skin obtained from Dr. John Varga at Northwestern, the Atit lab has identified an increase in number of dermal fibroblasts with activation of Wnt signaling. The Atit lab has focused on characterizing the fibrotic and vascular changes in adult mutant mouse skin to determine if it closely resembles lesional scleroderma skin. The skin changes in the adult mouse have been histologically characterized to demonstrate their similarity to human scleroderma skin. Dr. Atit's laboratory is now developing mouse models in which they can activate (and turn off) the Wnt signaling pathway in the adult mouse dermal fibroblasts in order to pinpoint the molecular changes that result in the initial development of skin fibrosis and the vascular defects. Dr Atit is collaborating with Dr. Howard Chang at Stanford University and Dr. Michael Whitfield at Dartmouth to test how closely the mutant tissue resembles scleroderma skin at the molecular level with respect to mRNA and microRNA expression pattern changes.

What this project means for people with scleroderma:

The dermal cell-specific induced mouse model with thickened dermis and avascular, fibrotic lesions provides a new opportunity to investigate the relationships between Wnt/beta-catenin signaling, dermal fibrosis and vascular abnormalities without an overt involvement of the immune system. Dr. Atit's lab can use these animals to define the cause of these changes in the skin at the molecular and cellular levels. If they are successful, the Wnt signaling pathway will be a new potential therapeutic target for treating skin fibrosis in scleroderma.

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