Airway remodeling is characteristic of diverse lung diseases including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and asthma. The pathogenesis of lung disease is multifactorial but common to all these disorders is epithelial injury and subsequent activation of pathways that promote epithelial regeneration. Progenitor cell expansion and lineage specification is critical for epithelial regeneration after injury. Thus, elucidating signaling pathways that govern progenitor cell growth and differentiation is fundamental to understanding disease pathogenesis. The broad, long-term objective of the current proposal is to identify molecular pathways that govern progenitor cell proliferation, survival and differentiation in the developing and remodeling lung epithelium. The goal of the current application is to elucidate molecular mechanisms underlying retinoblastoma family (Rb, p107 and p130) control of epithelial cell growth and differentiation during development and epithelial repair after injury. The central hypothesis is that p16 and p53 are critical downstream effectors of Rb in lung epithelial progenitor cells, and that Rb family proteins cooperatively regulate epithelial cell growth and differentiation by controlling distinct E2F target genes. Preliminary data demonstrate unique and overlapping Rb family functions in the lung epithelium that are associated with distinct gene expression profiles. Importantly, p16 is uniquely regulated by Rb and is induced in adult epithelial progenitor cell lineages that compensate for loss of Rb function. In addition, p16 has unexpected Rb independent functions critical for controlling progenitor cell growth. This proposal is designed to 1) test the hypothesis that increased p16 expression induced by aberrant growth signals such as Rb loss protects against deregulated progenitor cell growth, 2) test the hypothesis that p53 mediates an apoptotic response critical for suppressing aberrant pulmonary epithelial progenitor cell growth, and 3) identify E2F target genes differentially expressed in Rb family deficient lungs (separately and in combination) in order to elucidate molecular pathways governing epithelial cell growth and differentiation in vivo. Physiologic consequences of p16 and p53 loss will be determined in vivo using established models wherein Rb gene ablation is targeted to the lung epithelium in genetically modified mice. Mechanisms by which Rb, p16 and p53 regulate progenitor cell growth and differentiation will be determined in primary lung epithelial cell cultures and genetically defined cell lines. E2F regulated pathways that dictate Rb family dependent effects on pulmonary epithelial proliferation, apoptosis and lineage specification in vivo will be identified using mRNA microarray analysis. It is expected that these studies will provide fundamental insights into epithelial progenitor cell regulation and identify molecules with potential diagnostic, prognostic and therapeutic utility.
Chronic lung diseases affect >35 million Americans and thus are a significant cause of human morbidity and mortality. Airway remodeling after injury is common to all these lung disorders and must be precisely controlled to restore lung function. The proposed studies aimed toward elucidating mechanisms governing lung epithelial growth and remodeling will result in a better understanding of lung repair after injury and thus provide a foundation for development of novel therapies for lung disease.
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