Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY Silicosis and asbestosis are progressive fibrotic lung diseases causing respiratory failure. Effective therapies are inadequate in large part due to our limited understanding of disease pathogenesis. It is generally accepted that fibrosis arises from impaired regeneration of the alveolar epithelium after injury induced by silica and asbestos. Impaired epithelial regeneration ultimately leads to the activation of fibroblasts to deposit matrix. However, the critical regenerative defect underlying the pathogenesis of silicosis and asbestosis is unknown. Regeneration of the alveolar epithelium is orchestrated principally by alveolar type 2 epithelial cells (AEC2s). AEC2s proliferate then differentiate into AEC1s to restore normal alveolar structure. We and others identified a novel transitional state transiently assumed by regenerating AEC2s in mouse models of lung fibrosis. In most mouse models, transitional cells ultimately differentiate into AEC1s with resolution of fibrosis. However, murine and human silicosis and asbestosis are characterized by persistent transitional AECs with impaired AEC1 differentiation and nonresolving fibrosis. A fundamental unanswered question is why transitional cells retain capacity for AEC1 differentiation with resolving fibrosis in most mouse models but persist in the transitional state with nonresolving, progressive fibrosis in murine and human silicosis and asbestosis. We hypothesize that in mouse models of resolving fibrosis, proliferating AEC2s exit the cell cycle and transiently adopt the transitional state but retain the capacity to differentiate into AEC1s, restoring normal alveolar structure, whereas in silicosis and asbestosis, transitional AECs evolve into a distinct cell state characterized by specific marker genes and permanent cell cycle arrest, or senescence, lose capacity for an AEC1 fate, and promote nonresolving fibrosis. In Aim 1, we will test the hypothesis that in silicosis and asbestosis, transitional cells assuming this novel discrete state lose capacity to differentiate into AEC1s. We will define 2 subsets of transitional cells in murine and human asbestosis by their transcriptomes. We will perform lineage tracing to confirm that one subset of transitional cells differentiates into AEC1s, whereas the other subset persists in the transitional state indefinitely. In Aim 2, we will test whether specific signaling pathways prevent AEC1 differentiation from the transitional state, in turn activating fibroblasts to deposit scar. We will subject cell-specific, inducible knockout mice to silica and asbestos. Complementary studies in primary murine and human AECs will elucidate mechanisms that regulate cell fate and fibroblast activation. Examination of lung tissue from silicosis and asbestosis patients will confirm disease relevance. This work will fill a fundamental gap in our understanding of the mechanisms driving fibrosis in response to silica and asbestos inhalation and overcome a critical barrier to the development of novel therapies for silicosis and asbestosis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).