? ? This revised proposal describes a 5-year training program for the development of an academic career in Medicine. The principal investigator has completed a clinical/research fellowship in Pulmonary and Critical Care at Boston University, and is now transitioning to a career as an independent investigator. Alan Fine.M.D. will mentor the principal investigator's scientific development. Dr Fine is a recognized leader in lung biology, and has extensive experience training post-doctoral fellows, and graduate students. To ensure the Aims of this proposal are met the principal investigator has enlisted the expertise of Ken Walsh, PhD, and has put together a team of advisors that include Wellington Cardoso,MD, PhD, a recognized leader in lung development, and Dr Peter Quesenberry, an expert in stem cell biology. The overall objective of this proposal is to study a newly identified cell type isolated from the embryonic murine lung that has features of a mesenchymal stem/progenitor. These cells lack characteristics of mature mesenchymal cells, and can differentiate to smooth muscle, fat and cartilage during culture. While the overall frequency, and specific phenotype of these cells has yet to be determined, immuno-phenotyping data has localized these cells to the CD45(-),cytokeratin(-),CD31 (-) SP cell fraction of the lung. Notably, the molecular mechanisms maintaining these cells in an undifferentiated state are unknown; however, our pilot data suggest a role for the Foxo subfamily of transcription factors. These findings have led us to the following hypothesis: Contained with the embryonic lung are mesenchymal stem cells. These cells reside within the CD45(-)cytokeratin(-)CD31(-) SP fraction, have a unique phenotype, serve as precursors to differentiated mesenchymal cell types, and their state of differentiation is regulated by the Foxo subfamily of transcription factors. To test this we propose to: 1. Identify the cells contained within the embryonic lung that possess mesenchymal stem/progenitor activity. 2. Evaluate the in vivo capacity of these cells to differentiate to mature lung mesenchymal cell types. 3. Further explore the role of the Foxo subfamily in controlling the differentiation state of these cells. Together this proposal, coupled with the rich scientific environment offered at Boston University are designed to enable the principal investigator to meet the objectives outlined, advance his scientific background, and establish a career as an independent investigator. (End of Abstract) ? ? ? ?
Konter, Jason M; Parker, Jennifer L; Baez, Elizabeth et al. (2012) Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation. J Immunol 188:854-63 |
Ohashi, Koji; Parker, Jennifer L; Ouchi, Noriyuki et al. (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285:6153-60 |
Walkey, Allan J; Rice, Todd W; Konter, Jason et al. (2010) Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure. Crit Care Med 38:2329-34 |
Summer, Ross; Fiack, Christopher A; Ikeda, Yasumasa et al. (2009) Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol 297:L432-8 |
Murphy, Jaime; Summer, Ross; Wilson, Andrew A et al. (2008) The prolonged life-span of alveolar macrophages. Am J Respir Cell Mol Biol 38:380-5 |
Summer, R; Little, F F; Ouchi, N et al. (2008) Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. Am J Physiol Lung Cell Mol Physiol 294:L1035-42 |
Murphy, Jaime; Summer, Ross; Fine, Alan (2008) Stem cells in airway smooth muscle: state of the art. Proc Am Thorac Soc 5:11-4 |
Summer, Ross; Fitzsimmons, Kathleen; Dwyer, Daniel et al. (2007) Isolation of an adult mouse lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 37:152-9 |