Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Thesis (D.P.H.)--University of Michigan, 1994.

Thesis (M.S.)--University of Michigan, 1990.

Thesis (D.P.H.)--University of Michigan, 1994.

Thesis (doctoral)--University of Copenhagen.

Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (M.S.)--University of Wisconsin--Madison, 1981. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 125-127).

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

The clock-controlled nuclear receptor REV-ERBα has emerged as a critical regulator of multiple pathways involved in metabolism, development and immunity. Recent evidence has highlighted a major role for the clock in epithelial cells regulating lung inflammation, mediated by control of neutrophil chemokine expression. In this thesis, I examined the role of REV-ERBα in pulmonary immunity, using in-vivo gene targeting and nebulised lipopolysaccharide (LPS), a model for gram-negative bacterial infection, ex-vivo cell biology approaches and in vitro cell models. Initial studies of Rev-Erbα knock-out mice revealed an increase in pulmonary neutrophilia and inflammation upon aerosolised LPS challenge. Moreover, by selectively deleting the REV-ERBα DNA binding domain (DBD) in the mouse bronchial epithelium, I observed exaggerated inflammatory responses to LPS and augmented CXCL5 secretion. Interestingly, a dual deletion of REV-ERBα DBD and REV-ERBβ in mouse bronchial epithelium had a more dramatic effect on neutrophil recruitment and chemokine secretion than deletion of just the REV-ERBα DBD; in both basal and bacterial challenged conditions. Ex-vivo analysis revealed bronchial epithelial cells and macrophages both responded to novel REV-ERBα synthetic ligand GSK1362 but displayed divergent inflammatory responses in presence of this compound. Finally, I observed a striking loss of REV-ERBα protein upon pro-inflammatory challenge. Further analysis revealed this degradation was dependent on the 26S proteasome and driven by sumoylation and ubiquitination of REV-ERBα. However, by using novel REV-ERB ligand GSK1362, these post-translational modifications were blocked and the protein protected from degradation. Collectively, my results propose a new model for a central role for REV-ERBα in conferring clock control to lung neutrophilic inflammation. I have also identified a feed-forward circuit activated by inflammatory stimuli, leading to suppression of the endogenous anti-inflammatory REV-ERBα protein. Finally, I have discovered a novel mechanism for small-molecule regulation of REV-ERBα, operating via suppression of endogenous protein ubiquitination process. These observations implicate REV-ERBα as a novel therapeutic target in human inflammatory disease.