With the proposed Mentored Clinical Scientist Development Award the applicant will continue his investigations into basic mechanisms of lung inflammation. After two productive years in this laboratory the applicant remains firmly committed to a career in academic pulmonary medicine. The proposed research will allow the applicant to master a broad range of laboratory techniques in immunology, cell, and molecular biology. The research experience will be supplemented by a program of study of immunology and medical science. The project focuses on the development of inflammation and fibrosis following lung transplantation and the role of chemokines in these processes. After a lung is transplanted there may be several types of injury to the graft, including ischemia-reperfusion injury, acute rejection, and chronic rejection. These immune mediated injuries contribute to the development of scarring of the airways, so called bronchiolitis obliterans (BO). Over 50% of all lung transplants will develop BO after transplantation, and this remains the major cause of morbidity and mortality after lung transplantation. Neutrophils have been shown to be a prominent component of ischemia-reperfusion injury while T lymphocytes are the primary mediators of both acute and chronic rejection. The proposed project will determine which chemokines are produced after transplantation and their contribution to the development of graft injury and subsequent BO. Further experiments will manipulate chemokine or chemokine receptor expression in animal models of lung transplantation to investigate their role in the development of graft injury and BO. The applicant specifically proposes to: (1) investigate the expression of chemokines and chemokine receptors in the lung following transplantation in patients with and without acute rejection and BO; (2) investigate the role of chemokines in the development of ischemia-reperfusion injury in the airways using the murine tracheal heterotopic model of lung transplantation; (3) investigate the role of chemokines in the development of acute airway rejection and the development of BO in the murine tracheal heterotopic model of lung transplantation; (4) develop a novel murine model of airway rejection and BO.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL072775-04
Application #
7099442
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Colombini-Hatch, Sandra
Project Start
2003-08-04
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$129,870
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Medoff, Benjamin D; Okamoto, Yoshihisa; Leyton, Patricio et al. (2009) Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am J Respir Cell Mol Biol 41:397-406
Medoff, Benjamin D; Seung, Edward; Hong, Sandra et al. (2009) CD11b+ myeloid cells are the key mediators of Th2 cell homing into the airway in allergic inflammation. J Immunol 182:623-35
Medoff, Benjamin D; Thomas, Seddon Y; Luster, Andrew D (2008) T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol 26:205-32
Medoff, Benjamin D; Wain, John C; Seung, Edward et al. (2006) CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function. J Immunol 176:7087-95
Medoff, Benjamin D; Seed, Brian; Jackobek, Ryan et al. (2006) CARMA1 is critical for the development of allergic airway inflammation in a murine model of asthma. J Immunol 176:7272-7
Medoff, Benjamin D; Seung, Edward; Wain, John C et al. (2005) BLT1-mediated T cell trafficking is critical for rejection and obliterative bronchiolitis after lung transplantation. J Exp Med 202:97-110