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   at Columbia University Medical Center
PROJECTS
Control of airway progenitor cell fate in development and regeneration  
Airways are lined by a balanced mixture of ciliated, secretory, basal and neuroendocrine cells crucial for lung homeostasis. How lung progenitors give rise to these cell types and how these fates are balanced in developing airways, remain an open question. By inactivating gene components of the Notch pathway in the mouse lung, we found that airways can no longer form secretory Clara cells and become overpopulated with ciliated cells and neuroendocrine (NE) cells. Postnatally Notch signaling also prevents abnormal excessive formation of mucous-secreting cells. We are currently investigating the mechanisms by which Notch controls specification of secretory cells and the signals that lead to the appearance of regionally distinct populations of secretory cells. We are also examining the mechanisms that give rise to NE cells and the impact of NE cells in modulating the phenotype of neighbor cells in the embryonic and postnatal lung. These studies led to the identification of a novel Clara-like progenitor cell associated with NE bodies early during airway development that in adult can give rise to both secretory and ciliated cells during homeostasis and after injury-repair. These findings provide insights into the mechanisms of airway regeneration and into the regulation of the secretory phenotype likely to be critical in the pathogenesis of conditions, such as asthma and chronic obstructive pulmonary disease (COPD), in which airways have overabundance of secretory cells.
 
Retinoic acid signaling in early lung development  
.Developmental defects, such as tracheoesophageal fistula, pulmonary hypoplasia and failure to form the lungs are known for decades to be part of the "Vitamin A deficiency syndrome." We have been studying the pathogenesis of these defects and the role of RA in lung formation. Our studies provide a comprehensive view of how RA influences embryonic lung development and reveal specific phases and sites where RA is required in the embryonic lung. The observations included the first mapping of key components of the RA pathway during lung morphogenesis with sites of synthesis, RA receptor (RAR) expression and activation, and potential sites of RA metabolization. We generated a number of relevant model to address questions on when and how RA is critical for the lung. Among these was the establishment of a foregut culture system to study lung initiation, the generation of RAR constitutively active chimeric transgenic mouse models. We have also generated a comprehensive database of RA-dependent genes present in the foregut at the onset of lung development, which we have been using to explore specific RA-related mechanisms in lung organogenesis. Our results suggest that RA controls lung formation by balancing the effect of the Wnt and Tgfb pathways in Fgf10, a growth factor required for induction of lung buds. Disruption of Wnt-Tgfβ-Fgf10 interactions likely represents the molecular basis for the failure to form classically reported in vitamin A deficiency.
 
Regulation of airway smooth muscle formation in the developing lung  
.In a genome-wide screen for targets of RA during early lung development we found expression of smooth muscle (SM) markers significantly increased in RA-deficient embryos. Additional studies in vivo or in vitro using lung cell and organ cultures, as well as pharmacologic, genetic and dietary approaches uncovered a novel role for Vitamin A in restricting the SM differentiation program in the developing murine airways. The project investigates the molecular mechanism by which RA controls SM gene expression and ultimately the phenotype of the airway SM. Current studies focus on the identification of RA-dependent genes involved in epigenetic modifications and the characterization of the role of epigenetic mechanisms in SM gene expression in mesenchymal cells isolated from RA deficient and sufficient mice.
 
Mechanisms of initiation of the multiciliated cell phenotype in airway progenitors  
.Changes in number, morphology and function of multiciliated cells have been reported in multiple human conditions, including ciliopathies and and chronic obstructive pulmonary disease. Exposure to smoke or other environmental agents can disrupt the integrity and function of multiciliated cells, compromising mucociliary transport. Little is known about the molecular and cellular events that result in formation of multiciliated cells from respiratory progenitors and how diversity is established among multiciliated cells in different regions of the respiratory epithelium. Studies in this project address these questions focusing on the identification of the early signals required for commitment of airway progenitors to the multiciliated cell phenotype. Moreover, the project investigates the mechanisms that modulate the ciliated cell phenotype during injury-repair in animal models and   in pulmonary diseases.
 
Identification of early markers of lung epithelial lineages in differentiating murine and human ES and iPS cells  
.The ability to recognize early steps of differentiation of ES and iPS cells toward specific lung epithelial lineages has been limited in part by the availability of markers. This is further complicated by the fact that these lineages may actually encompass different subpopulations of cells. The project explores our databases of genome wide targets of key developmental signals and markers of lung epithelial lineages to detect early stages of commitment of ES and iPS cells into specific programs of differentiation. These markers can be used in differentiation assays in vitro or in vivo in repopulation studies with bioengineered lungs and in modeling diseases with iPS-based approaches.
 

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