The overall goal of this proposal includes a plan to foster the career development of Dr. Jessica Klekamp while understanding the investigation of a fundamental component of endotoxin mediated airway injury- neutrophil recruitment to the lung. Dr. Klekamp's long term career goal is to develop the education, research skills, and experience to become an independent physician-scientist capable of making a meaningful contribution in biomedical science. This award ,would allow her to fulfill her immediate goals of furthering her understanding of cellular interactions at the molecular level through course work, attaining new research skills in molecular biology, and continuing her investigation of leukocyte and endothelial cell adhesion molecules. This career development plan would take place in the ideal environment of the NIH-supported Specialized Center in Environmental Airway Disease, with Dr. David A. Schwartz as her mentor, the principal investigator for this specialized Center. This environment provides Dr. Klekamp both the resources and full access to the scientific expertise to make a significant contribution to the study of environmental lung disease. The proposed research project investigates the early pathogenic events that control movement of neutrophils from the vascular space to the airway, in an established murine model of endotoxin induced airway disease. While the role of leukocyte/endothelial cell adhesion molecules in neutrophil recruitment in the systemic circulation has been well defined, the involvement of these molecules in the pulmonary circulation is less well understood, and their specific role in inhaled LPS injury has not been studied. The overall hypothesis of this investigation is that a localized activated vascular endothelium serves to move the neutrophil from the pulmonary capillary circulation (and the bronchial post-capillary venules) to the airspace following inhalation of endotoxin.
The specific aims focus on the interaction of the neutrophil and the endothelium in a stepwise fashion beginning with activation of the endothelium, followed by activation of the neutrophil integrins and firm adhesion to the endothelium, and culminating in transmigration across the endothelial cell layer. The goal of this investigation is to determine whether interventions during each of these phases of neutrophil recruitment will effectively limit the inflammatory response, and prevent the pathophysiologic consequences of endotoxin mediated airway disease.
