Molecular control of a novel transitional cell state in alveolar regeneration

Duke University, Durham NC

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Abstract

Summary Distal lung diseases are a major cause of mortality and morbidity in the United States. Recurrent alveolar injury, dysregulated cell-cell communication, and altered cell intrinsic pathways in alveolar niche have been implicated in the pathogenesis of distal lung diseases. Although considerable progress has been made in mapping and cataloguing normal and aberrant cell states in lung diseases, the mechanisms that control regenerative versus maladaptive repair and the associated cell states remain incompletely understood. Recent studies including our own have identified repair associated transcriptionally distinct cell states that emanate from quiescent progenitors. We also found that disruption of epithelial transitional states impairs alveolar repair leading to pathological states resembling human lung diseases. Currently we lack a comprehensive understanding of the mechanisms that control regenerative versus maladaptive repair and the aberrant cell states found in lung diseases. Our preliminary data show that: i) oxidative stress pathway is transiently activated in PATS during repair in multiple injury models; ii) oxidative stress pathway is also activated in genetically induced PATS even in the absence of injury; iii) Glutathione peroxidase (GPX4), a key repressor of oxidative stress is expressed in quiescent AT2s but it is transiently downregulated at the onset of alveolar repair; iv) genetic loss of Gpx4 is sufficient to induce AT2s transition to PATS; and v) activation of NRF2 induces aberrant epithelial cells differentiation to AT1s. Based on these preliminary data, we hypothesize that a fine balance in oxidative stress responses is essential for alveolar epithelial cells differentiation and that Gpx4 maintains AT2s quiescence and represses their differentiation by suppressing oxidative stress. We also hypothesize that TP53 and NRF2 co- operate to define the degree of oxidative stress responses to control the fate of PATS during alveolar repair. Here, we propose an innovative program, built upon our published work as well as diving into new avenues, is poised to broaden our understanding of alveolar repair. The major goals of this proposal are: In Aim1, we will determine the role of oxidative stress in alveolar epithelial cell quiescence and plasticity. In Aim2, we will interrogate the genetic interaction between GPX4, NRF2, and TP53 in alveolar epithelial repair. In Aim3, we will study the dynamics of oxidative stress in normal and aberrant epithelial cells in human lungs. We will use genetic and pharmacological strategies, including newly established mouse models and models and cutting- edge profiling tools to study the role of GPX4, NRF2, and TP53 mediated pathways in alveolar epithelial cell fates. Our prior expertise in lung regeneration and transcriptional control of cell fates will aid us in studying the proposed goals. The outcomes from these proposed studies will have broader impact on lung regeneration and will reveal novel targets to treat lung diseases including pulmonary fibrosis.