During embryonic development the conducting airways of the lung are wrapped in a layer of contractile smooth muscle that maintains tone and regulates dilation and constriction of the tubes. Misregulation and hypertrophy of the airway smooth muscle is a key feature of serious diseases affecting the lung in postnatal life including asthma. Signals originating in the airway smooth muscle play an essential role in airway remodeling and mast cell invasion, resulting in the airway hyperresponsiveness observed in allergic asthma. A predisposition to asthma is associated with patterning defects that arise during fetal development, highlighting the need to understand the normal process of smooth muscle development at a cellular resolution to provide a framework for understanding mutant phenotypes and disease pathogenesis. The development and patterning of the airway smooth muscle is essential for proper lung function, yet little is known about the cell progenitors of this tissue, their developmental potential how they assemble into smooth muscle during development. Using conditional Cre-mediated recombination techniques to fluorescently mark single cells at defined times during lung development and follow the fate of their progeny, the experiments detailed in this proposal will identify when and where progenitor cells are specified to form airway smooth muscle, and will define the developmental potential of those smooth muscle progenitors. This clonal labeling technique will then be extended to lung organ explants, which will allow visualization of the marking event and continual tracking of the marked cell and its progeny during development in culture. These experiments will provide a cellular level understanding of how airway smooth muscle is formed, an understanding that I hope will lead in the long run to new avenues for diagnosis and treatment of asthma and other disease affecting smooth muscle lineages of the lung. ? Relevance: The cellular basis for airway smooth muscle hypertrophy in allergic asthma is not completely understood. Doubt has been cast on whether proliferation alone is responsible for the expansion of the smooth muscle layer, and other factors such as cell migration, induction, and decreased apoptosis may play key roles in airway remodeling. In addition to providing a clear understanding of the process of normal smooth muscle development, the techniques detailed in this proposal can be extended to define the cellular events responsible for airway remodeling in asthma models, thereby opening new avenues for the diagnosis and treatment of the disease. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10-H (20))
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Colombini-Hatch, Sandra
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Stanford University
Schools of Medicine
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Kumar, Maya E; Bogard, Patrick E; Espinoza, F HernĂ¡n et al. (2014) Mesenchymal cells. Defining a mesenchymal progenitor niche at single-cell resolution. Science 346:1258810