Grant: Project Grant

Scleroderma is an incurable and deadly autoimmune disease that causes scarring (fibrosis) of the skin and internal organs. Early in the disease, patients develop one of two main forms: a severe progressive type, and a form with a slower rate of damage. Patients with rapid disease progression have a death rate of up to 40% after 5 years, similar to aggressive types of cancer. The only effective treatment for these patients is a stem cell transplant, but many patients may not respond to it. The major obstacle to new, more effective treatments for scleroderma is a poor understanding of its root causes. We previously 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, is highly mutated in both scleroderma and in cancer. In cancer, MUC16 is known to promote inflammation and fibrosis, particularly when it interacts with its receptor, mesothelin (MSLN). In scleroderma, we found that MUC16 (normal and mutant forms) and MSLN levels are elevated. In our proposal, we aim to test our hypothesis that the interactions between MUC16 and MSLN promote fibrosis and inflammation. We propose that mutations in MUC16 increase the abnormal signals through MSLN to promote inflammation and fibrosis. We aim to evaluate the effects of these mutations on skin cells from patients with different forms of SSc, identify connections between specific MUC16 mutations and SSc symptoms and progression, and determine how MUC16 mutations affect inflammation and autoimmunity. Together, our studies may allow us to better understand how MUC16/MSLN 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 their diagnosis and subsequent treatment options.