Biomechanical and Biochemical Drivers of Scleroderma Fibrogenesis: Targeting Myofibroblast Resistance to Apoptosis to Reverse Established Fibrosis

David Legares, PhD
Massachusetts General Hospital and Harvard Medical School

Project Summary:

Fibrosis, or scarring of tissues, contributes heavily to the suffering and deaths caused by scleroderma. Whereas drugs capable of halting, or even just slowing, the progression of scleroderma fibrosis would be highly valuable additions to treatment options for this disease, the ultimate goal of scleroderma fibrosis drug development is to provide therapies that are capable of reversing established fibrosis, and consequently that are capable of making patients suffering from this disease better. Developing such therapies requires understanding how and why fibrosis is characteristically so persistent. We believe that one of the central reasons for this persistence is that fibroblasts, the cells that are responsible for producing scar tissue in scleroderma, become resistant to the normal process of dying when they are not needed, much in the way that cancer cells do.

Research Update:

Our group has tested this hypothesis in mouse models of scleroderma and we have found that specific cancer drugs may be able to overcome fibroblast resistance to death and reverse established fibrosis. These results suggest that specific cancer drugs may be able to reverse established fibrosis in the skin, lungs and other organs of scleroderma patients. Additionally, our group has developed the ability to determine which scleroderma patients might benefit from these drugs by testing fibroblasts obtained from biopsies of their fibrotic skin.

How This Work Will Impact Patients:

Our project aims to better understand how fibroblasts become resistant to normal cell death processes in scleroderma fibrosis; and then to develop treatment strategies to reverse established fibrosis in scleroderma by overcoming this resistance of scleroderma fibroblasts to normal cell death processes. It is our hope that this will lead to improved treatment options for patients living with scleroderma.

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