Role of Cortactin in Cigarette Smoke-Induced Lung Endothelial Dysfunction

Abstract: Cigarette smoking (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), and a key pathophysiological event in COPD development is dysfunction of the vascular endothelium. However, the mechanisms underlying COPD-associated endothelial dysfunction remain incompletely defined. Lung vascular endothelial cell (EC) responses to injurious stimuli such as CS (or e-cigarettes) are mediated by cellular cytoskeleton changes. CS exposure directly modulates EC barrier permeability, necrosis, and apoptosis through multiple signaling pathways involving cytoskeletal rearrangements. Cortactin (CTTN) is a central regulator of the actin cytoskeleton and an important modulator of lung EC function. Therefore, we hypothesized that characterizing the functional role of CTTN in lung EC responses to CS as a model of COPD pathogenesis will provide us with a better understanding of the molecular basis of COPD development, as well as potentially lead to the designing of novel therapeutic strategies. The current study explored the role of CTTN in lung EC signaling by using biochemical, biomechanical and biostructural approaches. The first innovative aspect of this project is that it establishes CTTN as a novel mediator of CS-induced lung dysfunction and addresses a previously undescribed role of CTTN in regulating lung EC apoptosis. The second innovative aspect is the use of the sophisticated imaging technique, Atomic Force Microscopy (AFM), to characterize the rheological properties of CTTN and its genetic variant in CS-induced lung dysfunction. The third innovative aspect of this study is the use of high end in silico methods to develop the previously unknown 3D structures of CTTN, identify its active sites, and provide further insights into key protein-protein interactions to better elucidate the CTTN structure-function relationship. Overall, this thesis work suggests that CTTN dysfunction may mediate CS/E-cigarette-induced lung EC apoptosis and provides new insights into the molecular basis of COPD development.