) 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003788-05
Application #
6530592
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Program Officer
Rothgeb, Ann E
Project Start
1998-03-10
Project End
2003-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
5
Fiscal Year
2002
Total Cost
$123,120
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Levy, Bruce D; De Sanctis, George T; Devchand, Pallavi R et al. (2003) Lipoxins and aspirin-triggered lipoxins in airway responses. Adv Exp Med Biol 525:19-23
Serhan, Charles N; Levy, Bruce (2003) Novel pathways and endogenous mediators in anti-inflammation and resolution. Chem Immunol Allergy 83:115-45
Levy, Bruce D; Serhan, Charles N (2003) Exploring new approaches to the treatment of asthma: potential roles for lipoxins and aspirin-triggered lipid mediators. Drugs Today (Barc) 39:373-84
Levy, B D; Serhan, C N (2002) Polyisoprenyl phosphates: natural antiinflammatory lipid signals. Cell Mol Life Sci 59:729-41
Levy, Bruce D; De Sanctis, George T; Devchand, Pallavi R et al. (2002) Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4). Nat Med 8:1018-23
Levy, B D; Clish, C B; Schmidt, B et al. (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2:612-9
Levy, B D; Serhan, C N (2000) Polyisoprenyl phosphate signaling: topography in human neutrophils. Biochem Biophys Res Commun 275:739-45
Levy, B D; Serhan, C N (2000) A novel polyisoprenyl phosphate signaling cascade in human neutrophils. Ann N Y Acad Sci 905:69-80
Clish, C B; Levy, B D; Chiang, N et al. (2000) Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J Biol Chem 275:25372-80
Sanak, M; Levy, B D; Clish, C B et al. (2000) Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur Respir J 16:44-9

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