Directional mucous flow by the mucociliary escalator is vital for clearance of secretions out of lungs. Dysfunction of mucociliary transport (MCT) is a central feature of Primary Ciliary Dyskinesias and plays an important role in the pathogenesis of airway diseases such as bronchiectasis. Normal airway regeneration following disease-associated injury, as well as every regenerative medicine approach to lung disease must restore directional MCT. We find that after airway injuries that leave the basal progenitor cells intact, te regenerated ciliated cells invariably re-establish their correct tissue polarity and resume MCT in the proper direction. However, a severe airway injury that requires extensive basal cell proliferation and migration results in disrupted mucociliary flow. The central hypothesis of this proposal is that directional mucociliary transport is preserved after regeneration by integration o inputs from the airway mesenchyme, basal cell-intrinsic polarity cues, and mucociliary flow. To test this hypothesis, this K08 proposes to (1) to establish whether the airway mesenchyme can determine MCT direction, (2) to determine whether airway basal cells define tissue polarity during regeneration, and (3) to determine whether fluid flow is sufficient to establish or refine proper MCT direction. At the completion of the project, these studies will clarify how this fundamental property of airways - directional mucociliary transport - is maintained after tissue injury and regeneration. These studies have immediate implications for bioengineering approaches to pulmonary regenerative medicine, and they may clarify pathophysiology of bronchiectasis and other airway diseases. Dr. Vinarsky is an Instructor in the Department of Medicine, Division of Pulmonary and Critical Care at the Massachusetts General Hospital (MGH), and his proposed 5-year mentored research plan will be performed in the laboratory of his primary mentor, Dr. Jayaraj Rajagopal at the Center for Regenerative Medicine, and in the laboratory of his co-mentor, Dr. Guillermo Tearney at the Wellman Center for Photomedicine. Dr. Vinarsky's background is in basic regenerative biology and pulmonary medicine, and his long-term career goal is to integrate his scientific and clinical expertise to study fundament problems of pulmonary biology and medicine. Under the mentorship of Dr. Rajagopal, a leader in airway stem cell biology, and Dr. Tearney, a world authority on optical coherence tomography and other advanced imaging technologies, Dr. Vinarsky has developed a research and training platform that will equip him with the intellectual skills and experimental approaches necessary to be productive in both mentored and independent settings. To accomplish his research and career goals, Dr. Vinarsky will take advantage of the expertise and resources of the Rajagopal and Tearney Laboratories, obtain formal training in imaging and developmental biology, establish collaboration and consultation with a team of experts, and acquire a relevant fund of knowledge through local and international meetings. The plan will be carried out in the Division Pulmonary and Critical Care Medicine, Center for Regenerative Medicine, the Wellman Center for Photomedicine, in a well-established environment for training physician-scientists.
Directional mucociliaty transport is a fundamental property of mammalian airways. This transport is disrupted in primary disorders of motile cilia, and likely in many other diseases of the airways. Directional mucociliary transport is also central to regenerative medicine approaches to lung diseases. The goal of this study is to examine how mucociliary transport is re-established after an airway injury and repair, with an emphasis on the role of the mesenchyme, basal cells, and fluid flow on preserving tissue polarity. This study has implications for bioengineering and we hope that they will ultimately lead to a better understanding of disease pathogenesis in bronchiectasis and other diseases of the airways.