Reduced anti-aging sirtuin in SSc: disease biomarker and therapeutic target

Scarring (fibrosis) in systemic sclerosis (SSc) results in progressive skin and lung damage. The mechanisms underlying fibrosis in SSc remain poorly understood, and effective therapies are lacking. Accelerated aging may be important factors contributing to scarring in SSc. We recently observed that a protein called SIRT1 is reduced in skin biopsies from some individuals with SSc. We hypothesize that low SIRT1 expression and function in SSc contributes to tissue scarring, and can be potential targets for treatment. To test this hypothesis, we will i) examine if reduced SIRT1 expression or function in patients with SSc is associated with disease complications, such as pulmonary fibrosis, or progressive disease in the skin and lungs; ii) evaluate the role of SIRT1 in experimental models of scleroderma using genetically-engineered mice; and iii) determine the effects, and mechanism of action, of a novel drug that activates SIRT1.These studies will fill important gaps in current knowledge. Moreover, our proposal is timely and relevant, as drugs to activate SIRT1 are currently in advanced stage clinical trials and might have potential role in the treatment of SSc.