The regulatory networks of human macrophages in healthy and fibrotic lungs

Pulmonary fibrosis is a leading cause of death in system sclerosis (Ssc). Recent work has suggested that lung macrophages play a key role in its development in SSc patients. Lung transplants performed on these patients as part of the Northwestern SSc program provide a unique opportunity to study these cells on the molecular levels in both the healthy donor and the diseased fibrotic lung. We plan first to use genomic assays to characterize the regulatory networks that control gene expression of lung macrophage populations from healthy individuals and compare this to previous data from mice. This comparison will provide an important resource for all lung diseases by setting the standard of normal function and informing on the applicability of mouse models for lung disease. Next, we will repeat the genomics assays on the macrophages from fibrotic lungs and identify regulatory elements that diverge between health and disease. Through computational analysis, we can propose candidate molecular regulators that reprogram the macrophages and implicate the signals to which they respond. These results will offer a better understanding of the disease environment and will likely lead to specific targets for therapy.