Using the Snail Transgenic Mouse to Elucidate Signaling Pathways Mediating Scleroderma Fibrogenesis

Colin Jamora, PhD
Univsersity of California San Diego

New Project Summary:

The ultimate goal of this project is to utilize a novel mouse model to elucidate the mechanism(s) by which fibrosis is initiated and maintained in the skin of patients. Insights gained from this study will illuminate new potential routes of therapeutic intervention against fibrosis, which is a major factor in the suffering and death of individuals with scleroderma. Despite the importance of fibrosis in this disease, current therapies have been largely disappointing and suggest that many more drug targets remain to be identified.

The Jamora lab is investigating fibrogenesis using a transgenic mouse engineered to artificially elevate the levels of the protein Snail in the cells of the epidermis in the skin. Snail is well known for its important role in the development of embryos and is recently receiving widespread attention for its contribution to the pathogenesis of a number of diseases such as cancer. Interestingly, Jamora's lab found that the skin of the Snail transgenic mouse develops fibrosis in the dermis of the skin even though Snail is expressed in the epidermis. Moreover, they were able to reconstitute this process with cells grown in a dish and demonstrated that Snail expressing epidermal cells secrete a factor(s) that can activate fibroblasts from the dermis to overproduce proteins that lead to fibrosis. As a result, the lab is poised to identify a novel pathway by which epidermal cells can instruct cells below them in the dermal compartment of the skin to mediate the development of fibrosis.  

With funding from the Scleroderma Research Foundation and two different collaborations facilitated by the SRF, Dr. Jamora's lab has focused recent efforts on validating the use of their Snail transgenic mouse as a bona fide model for scleroderma.  In collaboration with Dr. John Varga's laboratory at Northwestern University, they now have data that skin from patients with scleroderma do indeed express the protein Snail in their epidermis in a similar fashion to their mouse model. They have also collaborated with the laboratory of Dr. Michael Whitfield at Dartmouth University to assess whether the skin of the Snail transgenic mouse exhibits the same gene profile as human patients with scleroderma. Preliminary evidence suggests similarity between the mouse model and the diseased skin from humans with scleroderma.

Buoyed by the continuity of the Snail transgenic mouse with scleroderma skin, the Jamora lab has begun to analyze the proteins that mediate the cross talk between Snail expressing epidermal cells and dermal fibroblasts. Among the proteins they are analyzing is mindin (aka spondin-2) which is released from epidermal cells expressing Snail. When dermal fibroblasts sense mindin, they activate the transcription factor NFkB, which is a well-known inducer of inflammation. Hence, they are investigating the novel role of mindin as a mediator of inflammation and collagen production that characterizes the early stages of scleroderma.

What this project means for people with scleroderma:

This project has the potential of illuminating new players that mediate the onset and progression of fibrosis in patients with scleroderma. The idea that a protein(s) is released from epidermal cells to induce dermal fibroblasts to produce "scars" in the tissue is a paradigm shift and offers new avenues for drug development. Furthermore, the identification of proteins that are secreted outside of the cell that mediates the development and/or maintenance of fibrosis render them more accessible for therapeutic targeting.

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