Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD) is a devastating disease due to abnormal repair of the lung tissue, leading to scarring. Wnt/β-catenin is an important core pathway during normal human development and is abnormally altered in systemic sclerosis. Our lab was one of the first to link abnormal Wnt/β-catenin pathway function to lung fibrosis. We demonstrated that genetic disruption of a key component of this pathway, Lrp5, is important in the process of lung scarring and that circulating white blood cells from pulmonary fibrosis patients showed abnormal high expression of Lrp5, correlating with worse disease outcome. Disruption of Lrp5/β-catenin activity in mice affected differentiation of lung white blood cells called macrophages after lung injury, preventing proper healing. Macrophages, the most abundant immune cells in the lungs, are critical for fighting infection and clearing debris after lung injury. Our findings indicate that Wnt/β-catenin signaling is important in maintaining macrophage maturation and function, which is an exciting new discovery. Our proposed studies will lead to the development of approaches to identify Systemic Sclerosis-ILD patients who are at risk for worsened prognosis and are most likely to benefit from Wnt/β-catenin inhibitors that modify lung macrophage differentiation and resolve fibrosis.
|Effective start/end date||4/1/17 → 3/31/19|
- Scleroderma Foundation (Agmt 02/22/17)