Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury

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ABSTRACT Tyrosine phosphorylation networks have been implicated in the regulation of epithelial cell plasticity, which is often induced by injury in multiple tissue types. Regeneration following injury is mediated by dynamic intercellular signaling among diverse epithelial progenitor cell populations and residual cells. Recent studies have revealed a significant role for cell plasticity mechanisms induced by injury where cells from one region contribute to repair of another region after severe and acute damage. Despite the identification of multiple region-specific progenitor cells activated following injury, the identity of molecules that might be therapeutically targeted in response to injury to promote activation of progenitor cell types has remained elusive. We recently showed that Abl kinases are highly activated in bronchial epithelial cells in response to pathogen-induced injury, and that Abl inactivation in a subpopulation of airway cells promotes intercellular signaling among lung epithelial cell progenitors to induce alveolar regeneration after bacterial pneumonia challenge. Further, we have recently found that inhibition of Abl kinases after airway damage induced by toxic agents (SO2 exposure) promotes basal cell proliferation and enhances differentiation. Together these data reveal for the first time a role for Abl kinases in regeneration of both the alveolar and airway epithelium after injury by pathogens and toxic agents. The overall hypothesis is that activation of the Abl kinases in response to injury promotes lung epithelial damage, and that Abl inactivation in lung epithelial progenitors promotes efficient and rapid regeneration and re-establishment of tissue architecture following injury. The specific aims are: 1. Evaluate the role of Abl kinases in the regulation of alveolar epithelium regeneration in response to pathogen-induced injury. To this end we will: A) evaluate the role of Abl kinases in alveolar regeneration in response to acute lung injury and assess the effectiveness of Abl inhibitors to enhance both residual progenitor cell proliferation as well as invoking plasticity of airway progenitors for efficient and rapid alveolar regeneration; and B) assess whether Abl1 targets the HIF1 transcription factor in response to alveolar injury and repair. 2. Define the Abl-dependent pathways implicated in airway epithelium regeneration. In this aim, we will A) evaluate whether Abl kinases modulate the response of the airway epithelium during injury and whether Abl inactivation functions to promote airway regeneration required to restore airway epithelial architecture and function; and B) identify Abl-regulated pathways altered in the regenerating airway epithelium and evaluate the role of selected Abl targets including Yap1 in the regulation of airway epithelial cell proliferation, differentiation, and survival after injury. These studies break new ground as they will define novel Abl-regulated pathways activated in response to injury and identify epithelial progenitors with enhanced cell plasticity in response to Abl inactivation, leading to regeneration of the lung epithelium.