Grant: Pro. Gr. - PA: Inst. of Musculoskeletal Health and Arthritis: IMHA Mandate Areas

Scleroderma is an incurable and deadly autoimmune disease that causes scarring (fibrosis) of the skin and internal organs. Early in the disease, patients can develop two different major courses: a rapidly progressive type, and a form of scleroderma with slower accumulation of damage. Patients with rapid disease progression have a death rate of up to 40% by 5 years, which rivals most aggressive types of cancer. The only effective treatment for those patients is a stem cell transplant, but many patients may not respond to it. The major obstacle to new, more efficient treatments of scleroderma is a poor understanding of the causes that drive the disease. We made a surprising discovery that patients with progressive forms of scleroderma develop large numbers of DNA mutations in their skin cells. Many of these mutations resemble those present in cancers. One particular protein, MUC16 (also known as cancer antigen 125, or CA125), is highly mutated in both scleroderma and in cancer. In cancer, MUC16 is known to promote inflammation and fibrosis. In our proposal, we aim to define how mutations in MUC16 promote the progression of fibrosis and inflammation in patients with scleroderma. Together, our studies may allow us to better understand how mutations in MUC16 (and other similar genes) play a role in the development of scleroderma. Our research may facilitate the development of novel treatment strategies for scleroderma, and ways to predict which patients will develop severe forms of the disease, which may inform the diagnosis and subsequent treatment options.