Bidirectional Signaling Networks in Pulmonary Silicosis

About This Grant

PROJECT SUMMARY / ABSTRACT Pulmonary silicosis is a progressive, fibrotic lung disease marked by the formation of granulomas— composed of activated macrophages, fibroblasts, and dense extracellular matrix. These structures progressively erode alveolar architecture, impair gas exchange, and can lead to respiratory failure requiring lung transplantation. Once considered rare, silicosis is now re-emerging as a public health crisis, with alarming reports of rapidly progressive disease in young countertop fabrication workers exposed to engineered stone dust. Since 2019, over 70 cases have been identified in California alone, many in individuals in their 30s and 40s, with at least 10 confirmed deaths (California Dept of Public Health, 2024). Despite the growing burden of disease, the molecular circuits that drive macrophage and fibroblast activation within granulomas remain poorly defined. To begin to address this gap, I have performed single-cell RNA sequencing at multiple time points in the silica model of granulomatous pulmonary fibrosis and identified previously unrecognized populations of fibroblasts and macrophages that emerge in this model. Surprisingly, fibroblast subsets display dynamic shifts in Pdgfra and Pdgfrb expression, suggesting a rewiring of PDGF responsiveness that may regulate their proliferation or fibrogenic activation. In parallel, these activated fibroblasts upregulate Csf1 and IL-34, ligands for the macrophage mitogen receptor Csf1r, raising the possibility that fibroblasts provide spatially restricted trophic support for macrophage survival and expansion within granulomas. This K08 proposal seeks to build on these preliminary data to dissect the cellular and molecular pathways that govern fibroblast and macrophage proliferation and fate determination in silica-induced lung injury. Aim 1 will define the role of PDGFR signaling in regulating alveolar fibroblast expansion and fate specification and use the uLIPSTIC model to identify direct cell–cell interactions that drive fibroblast state transitions. Aim 2 will investigate the origins, recruitment dynamics, and proliferative signals that give rise to emergent macrophage populations using bone marrow chimeras, lineage tracing, and conditional gene deletion strategies targeting CSF1R and cytokinesis regulators. To support this scientific program, the candidate will receive advanced training in myeloid immunobiology, spatial transcriptomics, and in vivo cell–cell interaction mapping—skills that are essential for building a research career focused on immune–stromal crosstalk in fibrotic disease. By integrating functional genomics with spatially resolved single-cell tools, this work will illuminate the signaling circuits that orchestrate pathologic cell expansion in the injured lung and identify new targets for therapeutic intervention in silicosis and related granulomatous diseases.