Caveolin-1 is a marker protein for caveolae and can be a regulator of intracellular signaling pathways that contribute to the pathogenesis of human diseases. In the present study, the structural and functional changes of the lung in caveolin-1 null mice (Cav-1-/-) were assessed. Respiratory mechanics, measured using a small animal ventilator, revealed heightened central airway resistance (Rn), tissue resistance (G) and tissue elastance (H) in response to inhaled methacholine. The respiratory hyperreactivity is associated with increased collagen deposition around central and peripheral airways in Cav-1-/- mice; however, no difference was found in smooth muscle α-actin quantity between mouse strains. Similar to our in vivo findings, tracheal rings from Cav-1-/- mice mounted on an isometric wire myograph exhibited enhanced maximum active contractile force without a change in sensitivity (EC50) to methacholine. Rho kinase (ROCK1/2), protein kinase C (PKC) and extracellular signal regulated kinase 1/2 (ERK1/2) signaling were assessed as possible sources of the enhanced airway reactivity observed in Cav-1-/- mice. Inhibition of Rho kinase markedly blunted in vivo lung function responses (Rn) and (G) and ex vivo smooth muscle responses to methacholine. In fact, inhibition of Rho kinase completely eliminated any difference in response between mouse strains. Thus, our data indicate that Cav-1 may regulate mechanisms, such as Rho/Rho kinase signaling, that determine airway smooth muscle contraction and airway fibrosis; thus, it could be an important regulator of airway biology and physiology in health and disease.

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Vascular smooth muscle cells (VSMC) in the healthy adult arterial wall are a highlydifferentiated cell type with low levels of proliferation. However, when activated these cells can undergo a phenotypic change to become proliferative, migratory and excrete higher levels of extra-cellular matrix. While this cellular change is an essential element of the adaptable vasculature, excessive proliferation of VSMC underpins the development of a number of disease states, including atherosclerosis and restenosis after balloon angioplasty. The activation of VSMC is dependent on intracellular signalling pathways broadly altering gene expression. A key feature of this process is the initial potent regulation of transcription factors such as Egr-1, c-Jun and Ets-1, which then drive further transcriptional changes resulting in phenotypic change. The aim of this thesis was to discover novel genes, particularly transcription factors, regulated early upon stimulation and to characterise their contribution to the activation of VSMC. A key stimulus for activation of VSMC is the release of fibroblast growth factor 2 (FGF-2). A microarray used to explore the effects of FGF-2 exposure demonstrated the extensive nature of transcriptional modulation. In addition, it highlighted a number of transcription factors that were not previously described in VSMC: p8, ATF-4 and SHARP-2. In particular, SHARP-2 was potently upregulated and was reconfirmed in animal models of vascular injury. The subsequent contribution these factors make to VSMC activation was also demonstrated. p8 strongly induced VSMC proliferation, while ATF-4 contributed to cytokine production and SHARP-2 potently downregulated VSMC differentiation markers. A second area that was explored related to a gene known as YRDC, which was found to be upregulated upon stimulation of VSMC. YRDC is highly conserved across almost all cellular life, however its function remains unknown. A number of novel splice variants of YRDC were discovered and demonstrated to be differentially regulated in VSMC upon stimulation. Further work to commence characterising its function showed that it interacts with key ribosomal proteins and most likely plays a role in regulating translation. The discovery of the relevance of these genes to vascular biology in addition to their transcriptional regulation makes an important contribution to increasing our understanding of the molecular mechanisms behind vascular remodelling.

Thesis (Ph. D.)--University of Nevada, Reno, 2006. / "August, 2006." Includes bibliographical references (leaves 102-110). Online version available on the World Wide Web.

Thesis (M.S.)--University of Nevada, Reno, 2007. / "May, 2007." Includes bibliographical references (leaf 40). Online version available on the World Wide Web.

Thesis (M. Med. Sc.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 72-82)

Thesis (M. Sc.)--Queen's University, 2001. / Includes bibliographical references (leaves 78-93).

Thesis (Ph. D.)--Virginia Commonwealth University, 2006. / Prepared for: School of Medicine. Bibliography: leaves 54-73. Also available online.

Theses (Ph. D.)--Marshall University, 2007. / Title from document title page. Includes abstract. Document formatted into pages: contains xiii, 124 pages including illustrations. Includes vitae. Bibliographical references at the end of Chapters 1-3.