Injured Lung and its Influence on Bone Marrow Cell Phenotype

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This proposal describes a five year training program for development of an academic career in laboratory medicine. I have completed a fellowship in pulmonary and critical care medicine at Brown University, received board certifications in both specialties, and will now expand my scientific skills by applying my knowledge of both subspecialties to research in repair of acute lung injury at Rhode Island Hospital, a major teaching affiliate of Brown University. This program will examine cell-to-cell communication between injured lung cells and bone marrow cells and mechanisms by which this communication aids in marrow cell-based lung repair of lung injury. Dr. Peter Quesenberry will mentor my scientific development; I will also receive guidance from expert consultants in stem cell biology and lung biology. Dr. Quesenberry is the director of the division of hematology and oncology at Rhode Island Hospital; he has trained numerous postdoctoral fellows and physician-scientists in stem cell-related projects. Research frm our laboratory has demonstrated that adult bone marrow cells home to injured murine lung and participate in the restoration of lung cells. We hypothesize that injured lung cells induce phenotypic modifications of marrow cells by release from lung cells and subsequent uptake by marrow cells of lung cell-derived microvesicles, thereby inducing marrow cells to assume a lung cell phenotype. The specific aims are: 1.We will define marrow cell populations that take up lung-derived microvesicles, focusing on whole bone marrow cells and certain populations of hematopoietic stem cells. 2. We will determine the component of lung-derived microvesicles (RNA, DNA, protein) that causes phenotypic modification of marrow cells. 3. We will define the influence of cell cycle on the ability of marrow cells to take up lung-derived microvesicles. 4. We will determine if transplantation of marrow cells that have taken up lung-derived microvesicles attenuates radiation and elastase-induced lung injury, thereby improving lung function. Our hypothesis is that marrow cells possess sufficient reparative properties to provide a novel therapeutic option for pulmonary diseases with few currently effective treatments. Rhode Island Hospital and Brown Medical School provide an ideal setting for training physician-scientists by incorporating expertise from diverse disciplines into customized training programs. Such an environment will maximize my potential to establish a scientific niche that will be the basis of my future academic career.