HL-131: To function as an intact barrier, epithelia must maintain constant cell numbers despite sometimes high rates of turnover. If the rate of cell death exceeds proliferation, epithelial barrier function could become compromised; if it lags behind proliferation, cells could amass into tumors. However, little is known about the molecular mechanisms that keep airway epithelial stem cells largely quiescent during homeostasis or in check after a regenerative response to prevent the tissue overcrowding and dysplasia associated with airway remodeling in chronic lung diseases like COPD and asthma. After airway epithelial injury, surviving epithelial cells spread out to maintain barrier function and secrete Wnt7b to induce fibroblast growth factor 10 (Fgf10) expression and proliferation in airway smooth muscle cells (ASMCs). Fgf10 secreted by the ASMCs then acts on surviving club cells to initiate epithelial repair by breaking quiescence and inducing proliferation. The objective of this project is to identify the key signals that keep this Wnt7b-Fgf10 signaling cascade silent during normal homeostasis or once regeneration is complete, but activate the Wnt7b-Fgf10 signaling cascade when airway epithelial injury is sensed. Recent work in the lung has identified a role for the Hippo tumor suppressor pathway in regulating airway epithelial stem/progenitor cell quiescence during normal homeostasis. In addition, it was shown that the Hippo pathway becomes inactivated in surviving airway epithelial cells when they spread out to maintain barrier function shortly after injury, likely to initiate repair. We therefore hypothesize, that the Hippo pathway keeps airway epithelial/stem progenitor cells quiescent during normal homeostasis by inhibiting activation of the Wnt7b-Fgf10 signaling cascade. We have identified substantial aberrant signaling of the above-described pathways in clinical samples of COPD. We further hypothesize that when surviving airway epithelial cells spread out, signals are transduced by integrins to induce Yap/Taz-mediated Wnt7b expression. Interestingly, the scaffolding protein integrin linked kinase (Ilk) has been proposed to be essential for the proper termination of liver regeneration by positively regulating the Hippo pathway. Based on these findings the overall goal of this proposal is to test the hypothesis that: Ilk in the airway epithelium maintains stem cell quiescence by positively regulating the Hippo tumor suppressor pathway to block activation of the Wnt7b-Fgf10 signaling axis and prevent airway remodeling as observed in chronic lung diseases.
In Specific Aim 1, we will test the hypothesis that the Hippo pathway blocks activation of the Wnt7b- Fgf10 signaling axis between airway epithelial progenitors and their niche during normal homeostasis.
In Specific Aim 2, we will test the hypothesis that during normal homeostasis Ilk positively regulates the Hippo pathway in airway epithelial cells, to inhibit activation of the Wnt7b-Fgf10 repair pathway.
In Specific Aim 3, we will determine whether human airway remodeling in COPD patients is associated with deregulated Ilk-Hippo- Wnt7b-Fgf10 signaling.
Asthma and chronic obstructive pulmonary disease (COPD) are chronic lung diseases and are leading causes of morbidity and mortality. These diseases are thought to involve a chronic injury-repair cycle that leads to improper regeneration and the eventual breakdown of normal airway and/or alveolar structure and function resulting in loss of respiratory function. To fulfill the promise of regenerative medicine in the lung, this study aims o identify the molecular mechanisms that keep stem cells quiescent during homeostasis or in check after a regenerative response to prevent airway remodeling
