Fibrogenic activation and memory in the lung mesenchyme

Project Summary Interstitial lung diseases (ILDs) including idiopathic and other forms of pulmonary fibrosis represent a major and growing medical burden. While FDA-approved therapeutics limit progression of fibrotic ILDs, they do not fundamentally alter the course of these diseases. A central element of fibrosis progression in ILDs is the persistent activation of fibroblasts to a fibrogenic state; whereas transient fibroblast activation promotes wound healing, aberrant and prolonged fibroblast activation promotes fibrotic ECM deposition and hinders restoration of cellular homeostasis in epithelial and hematopoietic compartments. Hence, understanding how fibroblasts become activated and then locked in fibrogenic states is central to the development more effective therapies for fibrotic ILDs. Based on extensive preliminary data demonstrating a key role for the transcription factor Runx1 in fibroblast activation and fibrogenic memory in mouse and human fibrotic lung tissue, we will test the central hypothesis that fibroblasts gain and maintain a memory of fibrogenic activation that primes them for amplified activation upon repeated injury, and that Runx1 plays a central role in this activation and fibrogenic memory. We propose to test this hypothesis in three specific aims. In the first aim we will use a mouse model to identify the location, abundance and specific transcriptional targets of Runx1 engagement during fibrosis initiation, resolution and persistence. In the second aim we will test whether conditional deletion of Runx1 attenuates fibrosis and fibroblast memory, diminishes persistent fibrosis in a repeated bleomycin injury model, and restores homeostatic states in mesenchymal and other lung compartments. In the final aim we will analyze human lung tissue and fresh sorted fibroblasts to delineate Runx1 engagement, targets and functional effects relevant to human disease. In both mouse and human tissue, we will seek to identify the role of mechanical and biochemical signals in conferring fibrogenic memory and Runx1 activation and will test established and investigational therapeutics for their capacity to erase fibrogenic memory. Together these studies will test the function and regulation of Runx1 in fibrogenic cell activation and memory in mouse models and human tissue, potentially identifying a novel targetable mechanism underlying fibrotic ILD progression.