Molecular mechanisms underlying upper airway patterning and tracheomalacia

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DESCRIPTION (provided by applicant): The goal of this application is to provide the minority applicant with additional training that will enable her to become an independent RO1 funded investigator. This investigator completed her PhD in Reproduction of Physiology, a postdoctoral training in Developmental Biology and is currently an instructor in the Division of Pulmonary Biology. During the execution of this project, the principal investigator will acquire expertise in mammalian pulmonary biology, mouse transgenic technology, histology and microscopy. Dr. Jeff Whitsett, Professor of Pediatrics and Director of the Perinatal Institute, will serve as a mentor for the principal investigator. Dr. Whitsett is an internationally recognized leader in the field of Pulmonary Biology. An advisory committee comprise of outstanding scientists, will advise on scientific activities and career development of the principal investigator. This project will be carried out in the Division of Neonatology and Pulmonary Biology at Cincinnati Children's Hospital Medical Center, which is committed to the candidate's academic career and provides an ideal training setting for her development as an independent investigator. The research environment within the division combined with resources across the hospital will maximize the potential for the investigator to establish a scientific niche in pulmonary biology. The research component of this application focuses on the mechanisms by which Wntless, a chaperone dedicated to secretion of Wnt ligands, governs airway morphogenesis. Deletion of Wntless in mouse respiratory tract results in absent tracheal and bronchial cartilaginous rings. Sox9, a master regulator of chondrogenesis, is not detected while the expression domain of Smooth Muscle Actin is expanded. This proposal will test the hypothesis that Wntless induces upper airway patterning by modulation of chondrogenic transcription factor Sox9 via a paracrine mechanism thus promoting differentiation of tracheal mesenchyme. The specific aims are: 1) to define the role of Wntless during tracheal development. This aim will identify Wnt ligands produced by the epithelium and secreted by Wntless. It will also define steps in tracheal chondrogenesis mediated by these ligands. 2) To determine if Wntless is required for cell fate specification of the tracheal mesenchyme. Using cell lineage tracing I will study the cell fate of the tracheal mesenchyme in vivo and I will determine in vitro if Wntless differentially regulates expression of chondrogenic and myogenic genes. 3) To determine the mechanism by which Wntless regulates Sox9 expression. Using embryonic tracheal explant culture I will determine if paracrine canonical or non-canonical signaling controls the expression of Sox9 in tracheal cartilage. These studies will provide critical insights into the poorly understood normal tracheal development and the etiology of tracheomalacia. Understanding how Sox transcription factors are directed by Wnt signaling to promote tracheal cartilage development will lay the foundation for novel cell based therapies to repair damaged or malformed airways. (End of Abstract)