This application is to foster collaborative research among four groups of investigators at two neighboring institutions that will develop definitive data about the potential usefulness of adult stem cells to treat important pulmonary diseases. The staff includes one group of investigators with expertise in the preparation and characterization of adult stem cells, two groups of investigators with expertise in animal models for diseases such as fibrosis and emphysema, and a fourth group with expertise in the development of viral vectors for correction of the genetic disease cystic fibrosis (CF). The research will focus on the special class of adult stem cells that can be isolated from a patient's own bone marrow and that are referred to as mesenchymal stem cells or marrow stromal cells (MSCs). The program project format will allow the investigators to advance the field by performing collaborative work that cannot be carried out with individual research grants. Three sub-populations of MSCs that are well characterized will be tested in an innovative co-culture system that assays quantitatively their potential for repairing damaged pulmonary cells. We will also explore the possibility that cell fusion may play a role in the repair of pulmonary cells by MSCs. In addition, it will use a new assay for competitive engraftment to determine which sub-population of MSCs engrafts most efficiently in lungs of immunodeficient mice. The three sub-populations of cells will be assayed for engraftment and differentiation in a model for lung damage by asbestos and in a tracheal explant model. The three sub-populations of cells will be tested for their effectiveness in repairing lung damage in an elastase model for emphysema. In addition, we will attempt to define the mechanisms by which MSCs engraft in lung. MSCs from patients with CF will be engineered to correct the gene defect and then tested to determine whether they can become functional ciliated epithelial cells. Of necessity, the investigators will have to quickly share data as their experiment progresses. For example, data will suggest which sub-populations of MSC should be tested in the other three projects. As another example, the experience developed with lentiviruses will make it possible to use viruses for tracking MSCs.
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