With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon his prior experiences investigating the biology of inflammation in the lung. Based on very positive experiences in the laboratory to date, the applicant is firmly committed to a career in academic pulmonary and critical care medicine. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The present proposal provides the applicant the opportunity to master a broad range of current laboratory techniques in molecular and cellular biology, supplemented by a program of didactic study of immunology. The research project proposed focuses on pathogenic mechanisms of pulmonary fibrosis. Pulmonary fibrotic disorders appear to be initiated by inflammation of the lower respiratory tract, which causes activation and proliferation of mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation of the lower respiratory tract, which causes activation and proliferation of mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation initiating at least some of these disorders. The research proposed is based on the hypotheses that the recruitment of T cells, their polarization toward the Th2 phenotype, and the consequent recruitment of eosinophils contribute to the pathogenesis of pulmonary fibrotic disorders The applicant specifically proposes to: (1) Investigate the role of the T cell chemoattractant IP-10 (interferon-induced protein of 10 kd) in T cell recruitment in BLM-induced fibrosis; (2) investigate the balance of Th1 versus Th2 responses in BLM-induced fibrosis, and the role of cytokines and co-stimulatory molecules in determining this balance; and (3) investigate the role of Th2 cytokines, and the eosinophil chemoattractants eotaxin and LTB4 (leukotriene B4), in eosinophil recruitment in BLM- induced fibrosis. The last area of the research proposed will include the generation of mice genetically deficient for the recently described murine LTB4 receptor.
| Kim, Nancy D; Chou, Richard C; Seung, Edward et al. (2006) A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis. J Exp Med 203:829-35 |
| Tager, Andrew M; Kradin, Richard L; LaCamera, Peter et al. (2004) Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10. Am J Respir Cell Mol Biol 31:395-404 |
| Tager, Andrew M; Bromley, Shannon K; Medoff, Benjamin D et al. (2003) Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 4:982-90 |
| Tager, A M; Dufour, J H; Goodarzi, K et al. (2000) BLTR mediates leukotriene B(4)-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J Exp Med 192:439-46 |
