) In """"""""Novel lung-derived chalones: biosynthesis and bioactions,"""""""" the candidate will test the hypothesis that lipoxins and 15-epi-lipoxins function together in healthy individuals to inhibit the adhesion of inflammatory cells to the pulmonary microvasculature, a molecular regulatory mechanism that is diminished in asthmatics. Accustomed to thinking of inflammatory lung diseases, such as asthma, as reflecting a micro-environment with an excess of pro-inflammatory molecules, it is also possible that this pathologic state is derived from a loss of down-regulatory species. The investigator proposes the following specific aims to test his hypothesis: 1. To establish the biosynthetic routes of lipoxins, 15-epi-lipoxins, and other novel chalones during human neutrophil and pulmonary microvascular endothelial cell transcellular biosynthesis, 2. To determine regulation of leukocyte-pulmonary endothelial cell interactions by these compounds, and, 3. To profile novel lung-derived chalones in (a) chronic stable human asthma, (b) aspirin-sensitive asthma and (c) with inhaled glucocorticoid treatment of asthma. The proposed MCSDA (KO8) will enable the candidate to further pursue the pathophysiology of inflammatory lung disease, an interest born of experiences in the care of asthmatics and previous studies in the Serhan laboratory. Because of the poor understanding of the pathobiology of pulmonary inflammation, patients with widely divergent histopathology receive non-specific treatment (e.g., glucocorticoids). The applicant is firmly committed to an academic career in the pursuit of pivotal regulatory mechanisms of inflammation because their elucidation will result in a more complete understanding of pulmonary disorders and will provide a framework for the targeting of novel therapeutic regimens. The exposure to state-of-the-art techniques in structural biochemistry, cell biology and molecular biology in the Serhan lab as well as the unique resources afforded by Brigham and Women's Hospital and Harvard Medical School should facilitate the successful execution of the proposed research under the guidance of his scientific advisory committee, composed of Professors Charles Serhan, Morris Karnovsky, Jeffrey Drazen, and Michael Gimbrone. This MCSDA will provide him with the training required to become an independent scientific investigator, combining basic research, teaching and clinical duties, as he pursues a full-time career in an academic medical center.
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